Cellulose powder

ABSTRACT

Cellulose powder having an especially excellent balance among moldability, fluidity and disintegrating property is provided. Cellulose powder having an average polymerization degree of 150-450, an average L/D (the ratio of the major axis to the minor axis) value of particles of 75 μm or less of 2.0-4.5, an average particle size of 20-250 μm, an apparent specific volume of 4.0-7.0 cm 3 /g, an apparent tapping specific volume of 2.4-4.5 cm 3 /g, and an angle of repose of 55° or less.

CROSS-REFERENCE PARAGRAPH

The present application is a Divisional Application of pending U.S.patent application Ser. No. 10/332,245, which is a U.S. National Stageof PCT/JP2001/005576, filed on Jun. 28, 2001, which are incorporatedherein by reference in their entireties, which claim priority ofJapanese Patent Application No. 2000-204000 filed on Jul. 5, 2000.

TECHNICAL FIELD

The present invention relates to cellulose powder suitable as anexcipient for compression molding in medicinal, food and industrialapplications. More particularly, the present invention relates tocellulose suitable as an excipient for compression molding that hasexcellent fluidity and disintegrating properties while retaining goodcompression moldability, when used in medicinal application; and to anexcipient comprising the cellulose.

BACKGROUND ART

Tabletting of a drug has advantages such as high productivity and easyhandling of the resulting tablets during their transportation or upontheir use. Therefore, an excipient for compression molding needs to havesufficient moldability to impart such hardness that the tablets are notworn away or destroyed during their transportation or upon their use.Tablets used as medicine are required to be uniform in drug content pertablet in order to accurately exhibit their efficacy. Therefore, whenmixed powder of a drug and an excipient for compression molding iscompressed into the tablets, a uniform amount of the powder should bepacked into the die of a tabletting machine. Accordingly, the excipientfor compression molding needs to have not only moldability but alsosufficient fluidity. Moreover, the tablets as medicine should have notonly the properties described above but also a short disintegration timeto rapidly exhibit their efficacy after taking. With an increase of therate of disintegration, the medicine is dissolved more rapidly indigestive fluid, so that the transfer of the medicine into blood is morerapid, resulting in easy absorption of the medicine. Therefore, theexcipient for compression molding should have rapid disintegratingproperty in addition to moldability and fluidity.

Many active ingredient materials cannot be molded by compression andhence are tabletted by blending with an excipient for compressionmolding. In general, the larger the amount of the excipient forcompression molding blended into the tablets, the higher the hardness ofthe resulting tablets. The higher the compression stress, the higher thestrength of the resulting tablets. Crystalline cellulose is often usedas an excipient for compression molding from the viewpoint of safety andthe above-mentioned properties.

When an active ingredient and the like which are poor in moldability aretabletted in the field of medicine, an excessive compression stress isunavoidably applied attain a practical tablet hardness. The excessivecompression stress on a tabletting machine accelerates the abrasion ofdies and punches, and the disintegration time of the resulting tabletsis increased. For example, where an amount of an active ingredient, suchas a drug, to be blended is large (i.e. where the starting powder has alarge specific volume) such as a Chinese orthodox medicine, is blended,or where tablets are miniaturized so that the tablets are taken moreeasily, the problems, such as abrasion or destruction of the tabletsduring their transportation, are caused since the amount of an excipientblended is so remarkably limited, that desirable tablet hardness cannotbe attained. Moreover, there is, for example, the problem that when theactive ingredient to be used is that sensitive to striking pressure,such as an enzyme, antibiotic or the like, the active ingredient isinactivated by heat generation by striking pressure or striking pressureper se, it cannot be formulated into tablets because its content isdecreased in an attempt to attain a practical hardness. In order tosolve such problems, an excipient for compression molding is desiredwhich has sufficient fluidity and disintegrating property and has amoldability higher than before, which can impart a sufficient tablethardness even when added in a small amount, or impart a sufficienttablet hardness even at a low striking pressure.

For cellulose powder used as an excipient for medicine, compressionmoldability, disintegrating property and fluidity are desired to besatisfactorily high at the same time. However, since compressionmoldability and the other properties, i.e., disintegrating property andfluidity are contrary to each other, no previous cellulose powder thathas a high moldability has exhibited excellent disintegrating propertyand fluidity.

Cellulose powder, crystalline cellulose and powdered cellulose have beenknown and used in medicinal, food and industrial applications.

JP-B-40-26274 discloses crystalline cellulose having an averagepolymerization degree of 15 to 375, an apparent specific volume of 1.84to 8.92 cm³/g and a particle size of 300 μm or less. JP-B-56-2047discloses crystalline cellulose having an average polymerization degreeof 60 to 375, an apparent specific volume of 1.6 to 3.1 cm³/g, aspecific volume of 1.40 cm³/g or more, a content of powder of 200-meshsize or more of 2-80 wt % and an angle of repose of 35-42°. DE2921496discloses that cellulose powder having an average polymerization degreeof 150 is produced by carrying out acid hydrolysis of a cellulosematerial in the form of flowable, non-fibrous and water-insolublecellulose powder to adjust the solid content to 30-40 wt %, followed bydrying on trays at 140-150° C. RU2050362 discloses a process in which inorder to produce a stable gel of powdered cellulose, powdered cellulosehaving an average polymerization degree of 400 or less is obtained byimpregnating a starting material containing cellulose with a mineralacid or an acid salt solution, and then hydrolyzing the startingmaterial at a high temperature while stirring a starting material layerat a shear rate of 10-1,000 s⁻¹ for 1-10 minutes. The crystallinecelluloses and powdered celluloses concretely disclosed in thesereferences, however, are disadvantageous in that the average L/D valueof particles of 75 μm or less after drying, the apparent specific volumeand the apparent tapping specific volume are so small that thecompression moldability is low.

JP-A-63-267731 discloses cellulose powder having a certain averageparticle size (30 μm or less) and a specific surface area of 1.3 m²/g ormore. This cellulose powder involves the following problems because itis produced through a grinding step: its moldability is insufficientbecause the average L/D value of particles of 75 μm or less is small;its fluidity is low because its particles are small and light; and itsdisintegrating property is very low because its apparent tappingspecific volume is too low.

JP-A-1-272643 discloses cellulose powder having a specified crystal form(cellulose I type), a porosity for pores with a diameter of 0.1 μm ormore of 20% or more, and a content of powder of 350-mesh size or more of90% or more. JP-A-2-84401 discloses cellulose powder having a crystalform of type I, a specific surface area of 20 m²/g or more, a totalvolume of pores with a diameter of 0.01 μm or more of 0.3 cm³/g or more,and an average particle size of at most 100 μm. Although they have arelatively high moldability, these cellulose powders, however, aredifferent from the cellulose powder of the present invention as the L/Dvalue of dried powder is less than 2.0. In addition, the cellulosepowders are not desirable because the nitrogen specific surface area oftheir particles is too large, so that their conduits are decreasedduring compression, resulting in low disintegrating property. Moreover,the cellulose powders disclosed in the above references are obtained byhydrolysis followed by spray drying using an organic solvent as a mediumfor a slurry before drying. These powders have not been put to practicaluse because the use of the organic solvent requires, for example, adryer having an explosion-proof structure and a system for recoveringthe organic solvent and hence entails high cost.

JP-A-6-316535 discloses crystalline cellulose obtained by acidhydrolysis or alkali oxidative decomposition of a cellulosic material,which has an average polymerization degree of 100-375, an acetic acidretention of 280% or more, compression characteristics represented byKawakita's equation wherein the constants a and b are 0.85-0.90 and0.05-0.10, respectively, an apparent specific volume of 4.0-6.0 cm³/g, aspecific volume of 2.4 cm³/g or more, a specific surface area of lessthan 20 m²/g, substantially no particles of 355 μm or more, and anaverage particle size of 30-120 μm. The crystalline cellulose powderdisclosed in the above reference is described as having an excellentbalance between moldability and disintegrating property. The angle ofrepose of the concretely disclosed crystalline cellulose powder of anexample having the best balance between moldability and disintegratingproperty is measured and found to be more than 55°. The fluidity of thiscrystalline cellulose powder is thus not satisfactory. Particularly whenmolded under a high striking pressure, the crystalline cellulosedisclosed in the above reference can be given a high hardness but hasthe following problems: the water vapor specific surface area ofparticles after drying is so small that the conduits in the resultingtablets is decreased to retard the disintegration of the tablets; and inthe case of, for example, a recipe in which the proportion of an activeingredient having a low fluidity is high, the coefficient of variationof the weight of the resulting tablets is increased because of the lowfluidity to affect the uniformity of the content of a drug.

In addition, JP-A-11-152233 discloses crystalline cellulose having anaverage polymerization degree of 100-375, a content of particles capableof passing through a 75-μm screen and remaining on a 38-μm screen of 70%or more based on the total weight of the crystalline cellulose, and anaverage L/D (the ratio of the major axis to the minor axis) value ofparticles of 2.0 or more. This reference, however, does not describe theangle of repose of the crystalline cellulose disclosed therein. Thecrystalline cellulose specifically disclosed which is obtained bysieving the crystalline cellulose disclosed in JP-A-6-316535 hasproblems of worse fluidity and disintegrating property than thecrystalline cellulose of JP-A-6-316535 itself. JP-A-50-19917 discloses aprocess for producing an additive for molding tablets which comprisesdepolymerizing purified pulp to an average polymerization degree of450-650 by pretreatment, and subjecting the depolymerization product tomechanical grinding treatment until the apparent tapping specific volumebecomes 1.67-2.50 cm³/g and the particle size becomes such a value that50% or more of the particles pass through a 200-mesh screen. Thecellulose powder disclosed in this reference is disadvantageous in thatits polymerization degree is so high it exhibits fibrousness, theaverage L/D value of its particles of 75 μm or less and its apparentspecific volume are too large, so that it is poor in disintegratingproperty and fluidity. The fact that the apparent tapping specificvolume of this cellulose powder is small for its apparent specificvolume is also a cause for the deterioration of the disintegratingproperty of tablets obtained by compression.

As described above, no cellulose powder having moldability, fluidity anddisintegrating property at the same time with a good balance among themhas been known as conventional cellulose powder.

Medicine often has a form of a granular preparation such as granules orfine granules, to which a coating is applied to improve the stability ofan active ingredient, adjust the release rate of a drug, mask a taste,or impart enteric properties; or a form of a matrix type granularpreparation obtained by granulating a mixture of a coating agent and adrug together with other ingredients. When the granular preparation hasa particle size of about 1 mm or less, it is made into capsules in mostcases from the viewpoint of ease of handling, but it is preferably madeinto tablets by compression molding of a mixture of the granularpreparation and an excipient, from the viewpoint of cost and ease oftaking. However, when granules having a coating film, such as sustainedrelease coated granules, bitter-taste-masked granules, enteric coatedgranules or the like are tabletted by compression, there is thefollowing problem: the coating film is damaged by compression stress andhence the rate of dissolution and release is increased in mouth, stomachand intestines, so that the exhibition of an expected drug efficacy isnot achieved. In order to solve this problem, the following methods havebeen disclosed. JP-A-53-142520 discloses a method wherein crystallinecellulose is used. JP-A-61-221115 discloses a method wherein crystallinecellulose is used in a proportion of approximately 10-50% based on theamount of tablets. JP-A-3-36089 discloses a method wherein crystallinecellulose having an average particle size of 30 μm or less and aspecific surface area of 1.3 m²/g or more is used. JP-A-5-32542discloses a method wherein crystalline cellulose having a specificsurface area of 20 m²/g or more and a porous structure in which thetotal volume of pores having a diameter of 0.01 μm or more is 0.3 cm³/gor more. JP-A-8-104650 discloses a method wherein a microcrystallinecellulose having an average polymerization degree of 150-220, anapparent specific volume of 4.0-6.0 cm³/g, an apparent tapping specificvolume of 2.4 cm³/g or more, a specific surface area of less than 20m²/g, an acetic acid retention of 280% or more, a content of particlesof 355 μm or more of less than 5 wt %, a particle size distribution withan average particle size of 30-120 μm, compression characteristicsrepresented by Kawakites equation wherein the constants a and b are0.85-0.90 and 0.05-0.10, respectively, and such compression moldingcharacteristics that a cylindrical molded product with a base area of 1cm² obtained by compressing 500 mg of the crystalline cellulose at 10MPa for 10 seconds has a fracture strength in the direction of diameterof 10 kg or more (100 N or more in terms of a fracture strength in SIsystem of units) and a disintegration time of 100 seconds or less, isused.

The methods disclosed in JP-A-53-142520 and JP-A-61-221115, however, aredisadvantageous in that because of the low compression moldability ofthe microcrystalline cellulose, high compression stress is unavoidablyapplied in order to attain a practical hardness, so that the damage tothe coating film cannot be sufficiently prevented. The method disclosedin JP-A-3-36089 is disadvantageous in that the microcrystallinecellulose has a low fluidity and hence is apt to be separated andsegregated from granules during the preparation of tablets. Themicrocrystalline cellulose disclosed in JP-A-5-32542 is disadvantageousin that it is not practical due to high cost which attributes to the useof an organic solvent for the preparation thereof. In the case wherehigh compression stress cannot be applied, for example, the case wherethe strength of granules is low, the content of crystalline celluloseshould be increased in order to reduce the compression stress. In such acase, the crystalline cellulose disclosed in JP-A-8-104650 isdisadvantageous in that the use of the crystalline cellulose is limited,as it makes the disintegration of the resulting tablets very difficult.

Many active ingredients for medicine are often used after being madeinto fine particles, and have such a low fluidity that they are noteasily compression-molded by a direct compression method (a directstriking method). In particular, the larger the amount of the activeingredient for medicine to be added, the more difficult the compressionmolding. The above JP-A-8-104650 describes that the use of theabove-mentioned microcrystalline cellulose, a fluidizing agent and adisintegrating agent for Chinese orthodox medicine powder or crude drugpowder ensures enough fluidity to be subjected to a direct tablettingmethod, and thus makes it possible to produce tablets having anexcellent balance between moldability and disintegrating property.However, in the case where the content of an active ingredient formedicine having a low moldability, which is not limited to Chineseorthodox medicine powder or crude drug powder, is increased in apharmaceutical composition, there is still a problem that sufficientfluidity cannot be attained. Moreover, if the amount of a disintegratingagent is not sufficient, the retardation of disintegration and adecrease of the rate of dissolution occur. Since an active ingredientpowder for medicine is poor in compression moldability and cannot give amolded product without the addition of an excipient, a granulecompression method is generally adopted in which compressionmoldability, disintegrating property and fluidity are assured bycarrying out a step of granulating the active ingredient for medicinetogether with an excipient by a well-known wet or dry process, and thenthe resulting granules are compression-molded. An extra-granulationmethod is also often adopted as a means for enhancing the effect of theaddition of an excipient by adding the excipient outside the granulesbesides the excipient added inside the granules upon producing thegranules. JP-B-5-38732 discloses a crystalline cellulose having anaverage particle size of 30 μm or less and a specific surface area of1.3 m²/g or more. JP-A-8-104650 discloses a process for tabletting,using specific crystalline cellulose, by the granule compression method.These crystalline celluloses, however, are disadvantageous in that whencompression stress is increased, the disintegration is retarded and therate of dissolution is decreased.

DISCLOSURE OF THE INVENTION

The present invention is intended to provide cellulose powder havingvarious properties, i.e., moldability, fluidity and disintegratingproperty, at the same time with a good balance among them. Furthermore,the present invention is intended to provide the following tablets byincorporating said cellulose powder into the tablets: tablets havinghigh hardness without the retardation of their disintegration,especially when molded under a high striking pressure;granule-containing tablets having less destruction of granules, and lessdamages to the coating films of the granules and having only a slightchange in drug-releasing property when compression molded; and tabletswhich are uniform in their weight even when their drug content is high,and which have a good balance between hardness and disintegratingproperty.

In view of the situation described above, the present inventorsearnestly investigated and consequently succeeded in controlling thephysical properties of cellulose powder to be within specific ranges andfound cellulose powder having an excellent balance among variousproperties, i.e., moldability, fluidity and disintegrating property,whereby the present invention has been accomplished. The presentinvention is as follows:

(1) cellulose powder having an average polymerization degree of 150-450,an average L/D (the ratio of the major axis to the minor axis) value ofparticles of 75 μm or less of 2.0-4.5, an average particle size of20-250 μm, an apparent specific volume of 4.0-7.0 cm³/g, an apparenttapping specific volume of 2.4-4.5 cm³/g, and an angle of repose of 55°or less;

(2) the cellulose powder according to item (1), wherein the averagepolymerization degree is 230-450;

(3) the cellulose powder according to item (1) or (2), wherein theaverage polymerization degree is not a level-off polymerization degree;

(4) the cellulose powder according to any one of items (1) to (3),wherein the angle of repose is 54° or less;

(5) the cellulose powder according to any one of items (1) to (4),wherein the cellulose powder has a specific surface area of 85 m²/g ormore as measured by water vapor adsorption;

(6) the cellulose powder according to any one of items (1) to (5),wherein a breaking load of tablets obtained by compressing 0.5 g of thecellulose powder at 20 MPa is 170 N or more and the disintegration timeof the tablets is 130 seconds or less;

(8) a process for producing cellulose powder, comprising:

i) obtaining a cellulose dispersion containing cellulose particles,wherein

a) at an average polymerization degree is 150-450, and

b) the average L/D value in the wet state is 3.0-5.5, by controlling asolution-stirring force in hydrolyzing a natural cellulosic material orin a subsequent step, and

ii)spray-drying the thus obtained cellulose dispersion at an articletemperature lower than 100° C.;

iii) a step of drying the thus obtained cellulose dispersion;

(9) the process for producing cellulose powder according to item (8),wherein the average polymerization degree is 230-450;

(10) the process for producing cellulose powder according to item (8) or(9), wherein the average polymerization degree is not a level-offpolymerization degree;

(11) the process for producing cellulose powder according to any one ofitems (8) to (10), wherein the drying step is a step of spray drying atan article temperature lower than 100° C.;

(12) cellulose powder obtained by a production process according to anyone of items (8) to (11);

(13) an excipient comprising cellulose powder according to any one ofitems (1) to (7) and item (12);

(14) a molded product containing cellulose powder according to any oneof items (1) to (7) and the item (12) or an excipient according to item(13);

(15) the molded product according to the item (14), wherein the moldedproduct is tablets containing one or more active ingredients;

(16) the molded product according to the item (15), wherein the moldedproduct contains the active ingredient(s) in a proportion of 30 wt % ormore;

(17) the molded product according to any one of the items (14) to (16),wherein the molded product contains the active ingredient(s) vulnerableto compression;

(18) the molded product according to the item (17), wherein the activeingredient(s) is coated; (19) the molded product according to any one ofthe items (14) to (18), wherein the molded product is rapidlydisintegrable; and

(20) the molded product according to any one of the items (14) to (19),wherein the molded product contains a fluidizing agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described below in detail.

The cellulose powder according to the present invention should have anaverage polymerization degree of 150-450, preferably 200-450, morepreferably 230-450. When the average polymerization degree is less than150, the moldability of the cellulose powder is undesirablyinsufficient. When the average polymerization degree is more than 450,the cellulose powder shows remarkable fibrousness, so that its fluidityand disintegrating property are undesirably deteriorated. When theaverage polymerization degree is 230-450, the cellulose powder has anespecially excellent balance among moldability, disintegrating propertyand fluidity, and thus preferred. The average polymerization degree ispreferably not a level-off polymerization degree. When hydrolysis iscarried out to the level-off polymerization degree, the L/D value ofparticles is liable to be low by a stirring operation in a productionprocess, so that the moldability is undesirably deteriorated. The term“level-off polymerization degree” used herein means a polymerizationdegree measured by a viscosity method (a copper ethylenediamine method)after hydrolysis carried out under-the following conditions: 2.5Nhydrochloric acid, boiling temperature, and 15 minutes. It is known thatwhen a cellulosic material is hydrolyzed under mild conditions, itsregion other than crystals permeable with an acid, i.e., the so-callednoncrystalline region is selectively depolymerized, so that thecellulosic material hydrolyzed has a definite average polymerizationdegree called a level-off polymerization degree (INDUSTRIAL ANDENGINEERING CHEMISTRY, Vol. 42, No. 3, p. 502-507 (1950)). After thepolymerization degree reaches the level-off polymerization degree, itdoes not become lower than the level-off polymerization degree even ifthe hydrolysis time is prolonged. Therefore, when the polymerizationdegree is not lowered by hydrolysis of dried cellulose powder under thefollowing conditions: 2.5N hydrochloric acid, boiling temperature, and15 minutes, it can tell that the polymerization degree has reached thelevel-off polymerization degree. When the polymerization degree islowered by the hydrolysis, it can tell that the polymerization degreehas not yet reached the level-off polymerization degree.

The polymerization degree should be higher than the level-offpolymerization degree by preferably about 5 to about 300, morepreferably about 10 to about 250. When the difference is less than 5, itbecomes difficult to control the L/D value of particles to be within aspecific range, so that the moldability is undesirably deteriorated.When the difference is more than 300, the fibrousness is increased, togive inferior disintegrating property and the fluidity, which is notpreferred.

In the cellulose powder according to the present invention, the contentof particles capable of remaining on a 250-μm screen is preferably 50 wt% or less. Since particles of more than 250 μm form a dense structurewhen granulated, their presence in a proportion of more than 50 wt %undesirably deteriorates the moldability and the disintegratingproperty. The content is preferably 30 wt % or less, more preferably 10wt % or less, in particular, 5 wt % or less.

The average particle size of the cellulose powder of the presentinvention should be 20-250 μm. When the average particle size is lessthan 20 μm, the adhesive and cohesive properties of the cellulose powderare increased, resulting in not only difficult handling but also a lowfluidity. When the average particle size is more than 250 μm, thecellulose powder is separated and segregated from an active ingredient,so that the content uniformity of the resulting pharmaceuticalcomposition is undesirably apt to be decreased. The average particlesize is preferably 20-120 μm.

In the cellulose powder of the present invention, the average L/D valueof particles of 75 μm or less should be 2.0-4.5, preferably 2:2-4.2.When the average L/D value of particles of 75 μm or less is less than2.0, the plastic deformation properties and the moldability aredeteriorated, which is not preferred. When the average L/D value ofparticles of 75 μm or less is more than 4.5, the fluidity and thedisintegrating property are deteriorated, which is not preferred.Moreover, the moldability tends to be deteriorated probably because thecellulose fiber attains fibrousness and tends to have elastic recovery.

Average yield pressure is employed as an indication of the plasticdeformation properties of powder. The lower the value of the averageyield pressure, the higher the plastic deformation properties andcompression moldability of the powder. The highly moldable excipient ofthe present invention preferably has an average yield pressure of 35 MPaor less when 0.5 g of this powder is compressed to 10 MPa. When theaverage yield pressure is more than 35 MPa, the moldability isdeteriorated, which is not preferred. The average yield pressure ispreferably, in particular, 30 MPa or less.

The cellulose powder of the present invention should have an apparentspecific volume of 4.0-7.0 cm³/g. When the apparent specific volume isless than 4.0 cm³/g, the moldability is deteriorated. When the apparentspecific volume is more than 7.0 cm³/g, the disintegrating property andthe fluidity are deteriorated, which is not preferred. Moreover, themoldability tends to be deteriorated probably because the cellulosefiber attains fibrousness and tends to have elastic recovery. Theapparent specific volume is preferably 4.0-6.5 cm³/g, in particular,4.2-6.0 cm³/g.

The apparent tapping specific volume of the cellulose powder of thepresent invention should be 2.4-4.5 cm³/g, preferably 2.4-4.0 cm³/g, inparticular, 2.4-3.5 cm³/g. Even when the apparent specific volume is ina range of 4.0-7.0 cm³/g, if the apparent tapping specific volume isless than 2.4 cm³/g, the disintegrating property of tablets preparedfrom the cellulose powder are undesirably deteriorated because ofexcessive consolidation.

The cellulose powder of the present invention should have an angle ofrepose of 55° or less. When the angle of repose of the cellulose powderis more than 55°, its fluidity is remarkably deteriorated. Particularlywhen tablets are produced by blending a large amount of an activeingredient with poor fluidity, the weight variation of the tabletsbecomes remarkable if the fluidity of the excipient for compressionmolding is low, so that the tablets cannot be put to practical use. Theangle of repose of the cellulose powder of the present invention ispreferably 54° or less, more preferably 53° or less, in particular; 52°or less. The term “angle of repose” used herein means an angle of reposemeasured by a powder tester (mfd. by Hosokawa Micron Corporation) afteradjusting the water content of the powder to 3.5 to 4.5%. To impart suchhigh fluidity, the cellulose powder preferably has compressibility [%](=100×(apparent tapping density [g/cm³]−apparent density[g/cm³])/apparent tapping density [g/cm³]) in a specific range. Thecompressibility is preferably in a range of approximately 30-50%, morepreferably 30-49%, in particular, 30-47%.

The terms “apparent tapping density” and “apparent density” used hereinmean the reciprocal numbers of the apparent tapping specific volume andapparent specific volume, respectively, defined herein.

The cellulose powder of the present invention preferably has a specificsurface area of 85 m²/g or more as measured by water vapor adsorption.When the specific surface area is less than 85 m²/g, an area for waterinfiltration into particles is small and hence the amount of conduits ofthe tablets prepared from the cellulose powder is small, to lowerdisintegrating property of the tablets, which is not preferred. Althoughthe upper limit of the specific surface area is not particularlylimited, that of the cellulose powder before drying is about 200 m²/g asa measure because specific surface area is considered as a value whichis decreased by drying.

The cellulose powder of the present invention preferably has a specificsurface area in a range of 0.5-4.0 m²/g as measured by a nitrogenadsorption method. When the specific surface area is less than 0.5 m²/g,the moldability is deteriorated, which is not preferred. When thespecific surface area is more than 4.0 m²/g, the disintegrating propertyare remarkably 20 _deteriorated, which is preferred. The specificsurface area is preferably 0.8-3.8 m²/g, more preferably 0.8-3.5 m²/g.

When the nitrogen specific surface area is increased, spaces amongparticles (i.e. conduits) are crushed during compression, so that thedisintegrating property tend to be deteriorated. However, even if thenitrogen specific surface area is high, as long as the nitrogen specificsurface area is in a definite range, the amount of the conduits can bemaintained to prevent the deterioration of the disintegrating property,by controlling the water vapor specific surface area at a definite valueor more. A practical physical property value indicating the moldabilityis the hardness of a molded product. The higher this hardness, thehigher the compression moldability. A practical physical property valueindicating the disintegrating property is the disintegration time of amolded product. The shorter this disintegration time, the better thedisintegrating property. The balance between the tablet hardness anddisintegration time of a molded product obtained by compression at ahigh striking pressure is important in practice, considering that thedisintegrating property are generally deteriorated with an increase ofthe hardness and that the compression at a high striking pressure isunavoidable because many active ingredients for medicine or the likehave low moldability.

The breaking load in the direction of diameter of a cylindrical moldedproduct with a diameter of 1.13 cm obtained by compressing 0.5 g of thecellulose powder of the present invention at 20 MPa for 10 seconds ispreferably 170 N or more, more preferably 180 N or more, in particular,190 N or more. The disintegration time (a solution in pure water at 37°C., a disc is present) of the cylindrical molded product is preferably130 seconds or less, more preferably 120 seconds or less, in particular,100 seconds or less. The breaking load in the direction of diameter of acylindrical molded product with a diameter of 1.13 cm obtained bycompressing 0.5 g of a mixture of equal amounts of the cellulose powderof the present invention and lactose (Pharmatose 100M, available fromDMV Corp.) at 80 MPa for 10 seconds is preferably 150 N or more, morepreferably 170 N or more, in particular, 180 N or more. Thedisintegration time (a solution in pure water at 37° C., a disc ispresent) of this cylindrical molded product is preferably 120 seconds orless, more preferably 110 seconds or less, in particular, 90 seconds orless.

In addition, a cylindrical molded product with a diameter of 0.8 cmobtained by compressing 0.05 g of the cellulose powder of the presentinvention at 90 MPa for 10 seconds preferably has adsorptioncharacteristics represented by the following equation (1), after itsimmersion treatment with acetonitrile solvent:In(θe/(θe−θ)]=Ka·t   (1)wherein Ka≧0.0200 min⁻¹, θe is the saturated water vapor adsorption rate[%] of tablets at a relative humidity of 55% RH, and θ is the watervapor adsorption rate [%] of the tablets at a relative humidity of 55%RH and a water vapor adsorption time of t [min.]).

The term “immersion treatment with acetonitrile solvent” used hereinmeans immersing the cylindrical molded product in acetonitrile solventfor 48 hours to permeate the same with the acetonitrile solventsufficiently, and drying the cylindrical molded product at 25° C. in anitrogen stream until the relative humidity becomes 0% RH. In the casewhere the occurrence of moisture absorption or adsorption duringoperations is conjectured, for example, the case where the linearity ofthe equation (1) is low, the cellulose surface should be cleaned byvacuum drying with heat. When the Ka value is less than 0.0200 min⁻¹,the adsorption rate of water is slow, so that the disintegration timetends to be prolonged, which is not preferred. The effect of theimmersion treatment with acetonitrile solvent is conjectured as follows:The compression of the cellulose powder causes an increase ofinterparticle hydrogen bonds and crush of micro-spaces (conduits) inparticles. When the cylindrical molded product compressed to have a highdensity is immersed in acetonitrile, acetonitrile enters themicro-spaces (conduits) in particles but not sites of the interparticlehydrogen bonds to increase the diameter of the conduits.

That is, it can be speculated that with an increase of the number of theinner-particle micro-spaces (conduits) in the cellulose powder whichremain in tablets after the compression, the acetonitrile solventpermeates the cellulose powder more easily to increase the diameter ofthe conduits to give higher water vapor adsorption rate of the tablets.It can also be speculated that since such tablets adsorb water rapidly,their disintegration time in water is reduced. Although the upper limitof the Ka value is not particularly limited, the Ka value is preferably0.0400 min⁻¹ or less because with an increase of the Ka value, thedisintegration time tends to be reduced. The Ka value is preferably in arange of 0.0210-0.0400 min⁻¹, more preferably 0.0220-0.0400 min⁻¹.

A process for producing cellulose powder of the present invention needsto comprise: i) obtaining a cellulose dispersion containing celluloseparticles wherein, a an average polymerization degree of 150- 450, andb) the average L/D value in wet state is 3.0- 5.5, by controlling asolution-stirring force in hydrolyzing a natural cellulosic material orin a subsequent step, and ii) spray-drying the thus obtained cellulosedispersion at an article temperature lower than 100° C.

The natural cellulosic material referred to herein is a vegetablefibrous material derived from a natural material containing cellulose,such as wood, bamboo, cotton, ramie or the like and is preferably amaterial having a crystalline structure of cellulose I type. From theviewpoint of production yield, the natural cellulosic material ispreferably pulp obtained by purifying such natural materials andpreferably has an α-cellulose content of 85% or more.

Conditions for obtaining the cellulose dispersion having an averagepolymerization degree of 150-450 are, for example, carrying out thehydrolysis under mild conditions in a 0.1-4N aqueous hydrochloric acidsolution at 20-60° C. However, when the cellulosic material ishydrolyzed to the level-off polymerization degree, the L/D value ofparticles is liable to be decreased by stirring operation in theproduction process, so that the moldability is deteriorated, which isnot preferred.

Particles in the cellulose dispersion before drying preferably suchthat, have the average L/D value of the particles capable of remainingon 75- to 38-μm screens in a range of 3.0-5.5, more preferably 3.2-5.2,when sieved (through JIS standard screens) in a wet state. Sinceparticles in the cellulose dispersion are aggregated by drying,resulting in a small L/D value, cellulose powder having a highmoldability and good disintegrating property can be obtained by keepingthe average L/D value of particles before drying in a definite range.

The average L/D value of particles before drying can be kept in thedefinite range by controlling a stirring force in the hydrolyzingreaction or in a subsequent step at a specific intensity.

The stirring during the reaction or in the subsequent step shortenscellulose fiber. When the stirring is too vigorous, the average L/Dvalue of particles is decreased, so that no sufficient moldability canbe attained. Therefore, the stirring force should be controlled so thatthe average L/D value of particles becomes 3.0 or more. When thestirring is too mild, the fibrousness is enhanced, resulting in a lowmoldability and remarkably deteriorated disintegrating property.Therefore, the stirring force is preferably maintained so that theaverage L/D value of particles is not more than 5.5.

The intensity of the stirring force can be controlled, for example., inconsideration of P/V (kg·m⁻¹·sec⁻³) value obtained by the empiricalequation (2) described below.

The P/V value, however, is not an absolute numerical value because it isdependent on the size and shape of a agitation vessel, the size andshape of an agitating blade, the number of revolutions, the number ofturning blades, etc. The maximum value of P/V in each step before dryingranges from 0.01 to 10,000, and the lower and upper limits of P/V can bedetermined by controlling the number of revolutions, depending on thekind of the agitation vessel and the agitating blade. It is sufficientthat the lower and upper limits is properly determined by comparingvalues of P/V obtained by varying the agitation vessel used and thenumber of revolutions of the agitating blade with the average L/D valueof particles of 75 μm to 38 μm, for example, as follow: P/V is adjustedso as to fall within a range of 0.3 to 80 in the case where Np=8, V=0.03and d=0.3; P/V is adjusted so as to fall within a range of 0.01 to 5 inthe case where Np=2.2, V=0.07 and d=0.05; and P/V is adjusted so as tofall within a range of 1 to 10,000 in the case where Np=2.2, V=1 andd=1.P/V=(Nρ×ρ×n ³ ×d ⁵)/V   (2)wherein Np (−) is a power number of impeller, ρ (kg/m³) is the densityof a liquid, n (rps) is the number of revolutions of the agitatingblade, d (m) is the diameter of the agitating blade, and V (m³) is thevolume of the liquid.

The cellulose dispersion obtained by the above procedure should be madeinto powder by drying. The IC (electric conductivity) value of thecellulose dispersion before drying which has been washed and subjectedto pH adjustment after the reaction is preferably 200 μS/cm or less.When the IC value is more than 200 μS/cm, the dispersibility ofparticles in water is deteriorated, resulting in unsatisfactorydisintegration. The IC value is preferably 150 μS/cm or less, morepreferably 100 μS/cm or less. In preparing the cellulose dispersion,besides water, water containing a low proportion of an organic solventmay be used so long as it does not lessen the effect of the presentinvention.

For obtaining cellulose powder having a good balance among moldability,fluidity and disintegrating property, spray drying is preferablyconducted at an article temperature lower than 100° C. The term “articletemperature” used herein means exhaust temperature, not inlettemperature, in the spray drying. In the spray drying, aggregatedparticles in the cellulose dispersion after the reaction areconsolidated by heat shrinkage stress applied from all directions to bedensified (become heavy-duty) and attain a good fluidity. Furthermore,the aggregated particles attain good disintegrating property because ofweak hydrogen bonds among them. The concentration of the cellulosedispersion before the drying is preferably 25 wt % or less, morepreferably 20 wt % or less. When the concentration of the cellulosedispersion is too high, particles are excessively aggregated during thedrying and hence the average L/D value of the particles after drying isdecreased, so that the bulk density is increased to give a lowmoldability, which is undesirable. The lower limit of the concentrationof the cellulose dispersion is preferably 1 wt % or more. When the lowerlimit is less than 1 wt %, the fluidity is deteriorated, which is notpreferred. Moreover, such a lower limit is not desirable from theviewpoint of productivity because it raises the cost.

As compared with the drying method according to the present invention inwhich the spray drying is conducted at an article temperature lower than100° C., the methods as described in JP-A-6-316535 and JP-A-11-152233wherein a cellulose dispersion is heated at a temperature of 100° C. orhigher and then subjected to spray drying or drum drying, or a cellulosedispersion is dried in the form of a thin film without heating, are notpreferable because hydrogen bonds among aggregated particles are firmlyformed, so that the disintegrating property is deteriorated in thesemethods. In these methods, cellulose particles in a slurry are easilyaggregated in the state where the particles are arranged along thedirection of their major axis even if the L/D value of particles beforedrying is less than the lower limit of a specific range. Therefore, thedecrease of the L/D value of particles by drying can be suppressed togive good moldability. However, disintegrating property and fluiditycannot be imparted together with the moldability. Cellulose powderhaving good fluidity and disintegrating property in addition to goodmoldability can be obtained only by controlling the L/D value ofparticles to be within a specific range before drying and conductingspray drying at an article temperature lower than 100° C. Forcontrolling the L/D value of particles before drying to be within aspecific range, it is preferred to carry out hydrolysis under conditionswhere the average polymerization degree does not reach a level-offpolymerization degree, as described above.

In addition, for the cellulose powder obtained by drum drying or thinfilm drying, it is essential to grind it after the drying in order toimpart desirable powder physical properties. However, when all particlesare ground, the amount of static electricity generated by friction amongthe particles becomes large probably because the surfaces of theparticles become non-dense and uneven. This generation of a large amountof static electricity is not preferable because it also causesdeterioration of the fluidity. However, the cellulose powder may beground after the drying as long as the effect of the present inventionis not lessened.

A method in which a slurry before drying is dried after complete orexcessive replacement of a solvent in the slurry with an organic solventis not desirable because capillary force at the time of the evaporationof the organic solvent through spaces among particles is weak ascompared with water, so that the formation of interparticle hydrogenbonds is suppressed. Therefore, the nitrogen specific surface area isincreased too much to deteriorate the disintegrating property, which isnot preferred. The proportion of the organic solvent added is 50 wt % orless, preferably 30 wt % or less, in particular, 20 wt % or less, basedon the weight of the solvent in the slurry. Employment of a large amountof the organic solvent is not preferred because it requires large-scaleequipments such as an explosion-proof drying equipment and an equipmentfor recovering the organic solvent and hence entails a high cost.

The loss in weight on drying of the cellulose powder of the presentinvention is preferably in a range of 8% or less. When the loss inweight on drying is more than 8%, the moldability is deteriorated, whichis not preferred.

The excipient referred to herein is that used as a binder,disintegrating agent, granulation assistant, filler, fluidizing agent orthe like in the formulation of an active ingredient into apharmaceutical composition by a well-known method in medicinal, food orindustrial applications. The excipient is preferably an excipient forcompression molding having an excellent balance among compressionmoldability, disintegrating property and fluidity.

The molded product referred to herein is a molded product containing thecellulose powder of the present invention and obtained by processing bywell-known methods properly selected from mixing, stirring, granulation,compression into tablets, particle size regulation, drying, etc. Whenused in medicines, the molded product includes, for example, solidpharmaceutical compositions such as tablets, powders, fine granules,granules, extracts, pills, capsules, troches, cataplasmas, etc. Themolded product of the present invention includes not only moldedproducts used in medicines but also molded products used in foods (e.g.confectionery, health food, texture improvers, and dietary fibersupplements), solid foundations, bath agents, animal drugs, diagnosticdrugs, agrochemicals, fertilizers, ceramics catalysts, etc.

It is sufficient that the molded product referred to herein contains thecellulose powder of the present invention. Although the content of thecellulose powder is not particularly limited, it should be 1 wt % ormore based on the weight of the molded product. When the content is lessthan 1 wt %, satisfactory physical properties cannot be imparted to themolded product; for example, the molded product is worn away ordestroyed. The content is preferably 3 wt % or more, more preferably 5wt % or more.

Furthermore, the molded product referred to herein may freely contain,besides the cellulose powder of the present invention, other additivessuch as active ingredients, disintegrating agents, binders, fluidizingagents, lubricants, correctives, flavoring materials, coloring matters,sweeteners, surfactants, etc. if necessary.

The disintegrating agents include, for example, celluloses such assodium croscarmellose, carmellose, calcium carmellose, sodiumcarmellose, low-substituted hydroxypropyl cellulose, etc.; starches suchas sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheatstarch, corn starch, potato starch, partly pregelatinized starch, etc.;and crospovidone.

The binders include, for example, sugars such as white sugar, glucose,lactose, fructose, etc.; sugar alcohols such as mannitol, xylitol,maltitol, erythritol, sorbitol, etc.; water-soluble poly-saccharidessuch as gelatin, pullulan, carrageenan, locust bean gum, agar, konjakmannan, xanthan gum, tamarind gum, pectin, sodium alginate, gum arabic,etc.; celluloses such as crystalline cellulose, powdered cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, etc.; starches such as pregelatinized starch, starch paste,etc.; synthetic polymers such as poly(vinyl-pyrrolidone)s, carboxyvinylpolymers, poly(vinyl alcohol)s, etc.; and inorganic compounds such ascalcium hydrogenphosphate, calcium carbonate, synthetic hydrotalcite,magnesium aluminate silicate, etc.

The fluidizing agents include hydrated silicon dioxide, light silicicanhydride, etc. The lubricants include magnesium stearate, calciumstearate, stearic acid, sucrose fatty acid esters, talc, etc. Thecorrectives include glutamic acid, fumaric acid, succinic acid, citricacid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodiumchloride, 1-menthol, etc.

The flavoring materials include orange, vanilla, strawberry, yogurt,menthol, oils (e.g. fennel oil, cinnamon oil, orange-peel oil andpeppermint oil), green tea powder, etc. The coloring matters includefood colors (e.g. food red No. 3, food yellow No. 5 and food blue No.1), copper chlorophyllin sodium, titanium oxide, riboflavin, etc. Thesweeteners include aspartame, saccharin, dipotassium glycylrrhizinate,stevia, maltose, maltitol, thick malt syrup, powdered sweet hydrangealeaf, etc. The surfactants include phospholipids, glycerin fatty acidesters, polyethylene glycol fatty acid esters, sorbitan fatty acidesters, polyoxyethylenes, hydrogenated castor oil, etc.

The active ingredient referred to herein includes pharmaceuticallyactive ingredients, agrochemical ingredients, ingredients forfertilizer, ingredients for feed, ingredients for food, ingredients forcosmetic, coloring matters, flavoring materials, metals, ceramics,catalysts, surfactants, etc., and may be in any form such as powder,crystals, oil, solution or the like. The active ingredient may be thatcoated for, for example, the control of dissolution and release or thereduction of a bitter taste.

For example, the pharmaceutically active ingredients are thoseadministered orally, such as antipyretic analgesic antiphlogistics,hypnotic sedatives, sleepiness inhibitors, dinics, infant analgesics,stomachics, antacids, digestives, cardiotonics, drugs for arrhythmia,hypotensive drugs, vasodilators, diuretics, antiulcer drugs, drugs forcontrolling intestinal function, therapeutic drugs for osteoporosis,antitussive expectorants, antasthmatics, antibacterials, drugs forpollakiurea, tonics, vitamin preparations, etc.

The content of the active ingredient(s) in the molded product of thepresent invention is 0.01 to 99 wt % based on the weight of the moldedproduct. When the content of the active ingredient(s) is less than 0.01wt %, no sufficient drug efficacy can be expected. When the content ismore than 99 wt %, the content of the excipient is not sufficient, sothat satisfactory physical properties cannot be imparted; for example,the molded product is worn away or destroyed.

When the cellulose powder of the present invention is used in the casewhere the content of the active ingredient(s) in the molded product ishigh, it is especially advantageous because it has, for example, thefollowing advantages: it can impart a sufficient moldability withoutaccelerating the retardation of disintegration even at a high strikingpressure; it permits reduction of the amount of the cellulose powder tobe added and hence miniaturization of the molded product; and the degreeof wear of the resulting tablets is low and their powdering and breakageduring packing into bottles and transportation is minimal. The cellulosepowder of the present invention is advantageous when the content of theactive ingredient(s) is 5 wt % or more, preferably 10 wt % or more,still more preferably 30 wt % or more, in particular, 50 wt % or more.

Since the cellulose powder of the present invention has an excellentcompression moldability, it can be molded with a small blending amountthereof or a low compressive force and hence is very suitable fortabletting the active ingredient(s). The cellulose powder of the presentinvention enables the tabletting of a pharmaceutically active ingredientwith poor moldability, the miniaturization of large tablets of a Chineseorthodox medicine, crude drug, cold remedy, vitamin preparation or thelike, and the preparation of intraoral rapidly soluble tablets,granule-containing tablets, or the like.

The tablets referred to herein are molded products containing thecellulose powder of the present invention and optionally other additivesand obtained by any of a direct tabletting method, a granule compressionmethod and an extra-granulation method. Tablets obtained by directcompression are especially preferable.

The cellulose powder of the present invention is especiallyadvantageously used for an active ingredient for medicine having a lowmoldability, because of the advantages, for example, that compressioninto tablets can be carried out at a high striking pressure withoutaccelerating the retardation of disintegration. Whether the moldabilityis low or not can be determined by the hardness of tablets obtained byplacing 0.5 g of the pharmaceutically active ingredient in a die(manufactured by Kikusui Seisakusho Ltd. from material SUK 2,3) andcompressing the active ingredient with a flat punch and a base area of 1cm² (manufactured by Kikusui Seisakusho Ltd. from material SUK 2,3)until the pressure becomes 100 MPa (a static compressing machine such asPCM-1A manufactured by Aikoh Engineering Co., Ltd. is used and thecompression rate is approximately 20-30 cm/min). The cellulose powder ofthe present invention is especially effectively used when the tablethardness of the pharmaceutically active ingredient is less than 100 N,preferably less than 50 N, more preferably less than 10 N. Such a drugincludes phenacetin, acetaminophen, ethenzamide, etc.

When the cellulose powder of the present invention is used incombination with a fluidizing agent and a disintegrating agent, tabletsespecially excellent in moldability and disintegrating property can beproduced without deteriorating the fluidity during the production of thetablets. As the disintegrating agent, a super-disintegrating agent suchas sodium croscarmellose (e.g. “Ac-Di-Sol” manufactured by FMC Corp.) ispreferably used because it is effective even when added in a smallamount. As the fluidizing agent, light silicic anhydride is especiallypreferable, and the fluidizing agent includes “Aerosil” (mfd. by NipponAerosil Co., Ltd.), “Carplex” (mfd. by Shionogi & Co., Ltd.), “Cyroid”(mfd. by Fuji Davisson Co., Ltd.), “Adsolider” (mfd. by Freund SangyoK.K.), etc. Although the proportions of the components described aboveare not particularly limited, suitable examples thereof are as follows:the microcrystalline cellulose of the present invention 1 to 99 wt %,the disintegrating agent 0.5 to 20 wt %, and the fluidizing agent 0.1 to5 wt %.

It is preferable to adopt a method comprising premixing the activeingredient(s) and the fluidizing agent at first, mixing therewith thecellulose powder of the present invention, the disintegrating agent andoptionally other additives, and then making the resulting mixture intotablets, because this method gives higher fluidity and moldability thana method in which all the components are mixed at once. With a decreaseof the fluidity of the active ingredient(s) and an increase of theproportion of the active ingredient(s), the timing of addition of thefluidizing agent has a more remarkable effect.

Particularly when rapidly-disintegrating property is required, themolded product of the present invention is especially effective sincethe molded product of the present invention can have a sufficienthardness even when produced at a low striking pressure and thus may bemade thick, so that many conduits can be left in the molded product. Theterm “rapidly-disintegrating property” means that a molded product isdisintegrated within 1 minute in a medium such as water, artificialgastric juice, artificial intestinal juice, saliva or the like.Pharmaceutical compositions having such a characteristic includeintraoral rapidly-soluble tablets, intraoral rapidly-disintegrabletablets, etc.

The cellulose powder of the present invention is very suitable also fortabletting, for example, granules each having a coating film. When amixture of coated granules, the cellulose powder of the presentinvention and optionally other additives are made into tablets, apractical hardness can be attained even if the compression stress isgreatly reduced. Therefore, damages to the coating films by thecompression stress can be suppressed, so that the mixture can be madeinto tablets while enabling the granules to retain their expecteddissolving and releasing properties.

The active ingredient vulnerable to compression herein is, for example,an active ingredient which is inactivated by compression stress or heat,or an active ingredient which cannot exhibit expected dissolving andreleasing properties because the coating portion of the activeingredient is damaged by pressure.

The molded product containing a coated active ingredient(s) of thepresent invention refers to a molded product having the molded productform defined above, such as powder, granular preparations (e.g. finegranules or granules), or the like and containing one or more activeingredients, wherein the active ingredient(s) per se is coated with afilm; particles made of the active ingredient(s) and additives arecoated with a film; the active ingredient(s) is coated by granulating amixture of the active ingredient(s) and a coating agent; or the mixturethereof. The coating agent is used, for example, masking a taste,imparting sustained-release properties or enteric properties, orpreventing moisture, and includes, for example, cellulose type coatingagents (e.g. ethyl cellulose, hydroxypropylmethyl cellulose phthalate,carboxymethylethyl cellulose, hydroxypropylmethyl cellulose acetatesuccinate, cellulose acetate succinate, cellulose acetate phthalate, andcellulose acetate), acrylic polymer type coating agents (e.g. EudragitRS, Eudragit L and Eudragit NE), shellac and silicone resins. These maybe used singly or in combination. As a method for using these coatingagents, a well-known method may be used. The coating agent may bedissolved in an organic solvent or suspended in water. The coating agentsuspended in water may be freely granulated together with one or moreactive ingredients for medicine and other components.

With an increase of the proportion of the cellulose powder of thepresent invention blended in the molded product containing one or morecoated active ingredients of the present invention, the suppression ofthe damage to the coating film by the cellulose powder becomes moreeffective. The proportion to be blended is preferably 1 to 90 wt %. Whenthe proportion is less than 1 wt %, no sufficient effect can beobtained. When the proportion is more than 90 wt %, the proportion ofthe active ingredient(s) is undesirably insufficient. The proportion ismore preferably 5 to 80 wt %, in particular, 5 to 70 wt %.

The cellulose powder of the present invention can be used in wetgranulation as, for example, a reinforcing agent for a sugar coating insugar-coated tablets, an extrudability improver in extrusiongranulation, or a granulation assistant in crushing granulation,fluidized-bed granulation, high-shear granulation, tumblingfluidized-bed granulation or the like, and permits preparation of agranular pharmaceutical composition or granules to be compressed intotablets. For preparing the granules to be compressed into tablets, a drygranulation method may be adopted. In addition, tabletting by the methodwherein the cellulose powder of the present invention is added to suchgranules that are obtained by a well-known method and the mixture iscompression molded (an extra-granulation method) is also applicable.Since the cellulose powder of the present invention has high waterabsorption properties, the rate of granulation can be reduced even whena highly water-soluble pharmaceutical active ingredient is granulated.It, therefore, reduces the formation of coarse particles. and, thus,contributes to the increase of granulation yield. The cellulose powderof the present invention gives a bulky granulation product because ofits low particle density and hence contributes also to the preparationof granules for compression tabletting with high compressionmoldability. Furthermore, the cellulose powder of the present inventionmay be blended into a powder in order to, for example, prevent blockingor improve the fluidity, or it may be blended into capsules in order to,for example, improve the degree of filling.

The present invention is described in detail by way of the followingexamples, which did not limit the scope of the invention. Method formeasuring physical properties in the examples and comparative examplesare as follows.

1) Average Polymerization Degree

A value measured by the copper ethylene-diamine solution viscositymethod described in the crystalline cellulose identification test (3) inthe 13th revised Japanese Pharmacopoeia.

2) L/D of Particles Before Drying

The average L/D value of particles in a cellulose dispersion beforedrying was measured as follows. The cellulose dispersion was siftedthrough JIS standard screens (Z8801-1987), and a photo-micrograph ofparticles that had passed through a 75-μm screen and had remained on a38-μm screen was subjected to image analysis processing (apparatus:Hyper 700, software: Imagehyper, manufactured by Interquest Inc.). L/Dof the particles was defined as the ratio between the long side andshort side (long side/short side) of a rectangle having the smallestarea among rectangles circumscribed about any of the particles. As theaverage L/D value of the particles, the average of the L/D values of atleast 100 of the particles was used.

3) Loss in Weight on Drying [%]

After 1 g of powder was dried at 105° C. for 3 hours, the loss in weightwas expressed as a percentage by weight.

4) Proportion of Particles Capable of Remaining on a 250-μm Screen [(%)]

Using a low-tap type sieve shaker (Sieve Shaker Model A, mfd. by HeikohSeisaku-sho Co., Ltd.), 10 g of a sample was sifted through a JISstandard screen (Z8801-1987) with a screen opening of 250 μm for 10minutes, and the weight of particles remaining on the 250-μm screen wasexpressed as a percentage by weight based on the total weight.

5) Average L/D Value of Particles of 75 μm or Less

A photomicrograph of particles that had passed through a 75-μm JISstandard screen in sifting with Air Jet Sieve (Model A200LS, mfd. byALPINE) was subjected to image analysis processing (apparatus: Hyper700, software: Imagehyper, manufactured by Interquest Inc.). L/D wasdefined as the ratio between the long side and short side (longside/short side) of a rectangle having the smallest area amongrectangles circumscribed about any of the particles. As the average L/Dvalue of the particles, the average of the L/D values of at least 400 ofthe particles was used.

The average L/D value should be measured after previously making theparticles discrete so that they are not entangled with one another.

6) Apparent Specific Volume [cm³/g]

A powder sample was roughly packed into a 100-cm³ glass measuringcylinder over a period of 2-3 minutes by the use of a metering feeder orthe like, and the top surface of the powder layer was made level with asoft brush such as a writing brush, after which the volume of the powdersample was read. The apparent specific volume was expressed as a valueobtained by dividing the read value by the weight of the powder sample.The weight of the powder was properly determined so that its volumemight be approximately 70-100 cm³.

7) Apparent Tapping Specific Volume [cm³/g]

Using a commercial powder physical property measuring machine (PowderTester Model T-R, mfd. by Hosokawa Micron Corporation), a 100-cm³ cupwas filled with powder and tapped 180 times. Then, the apparent tappingspecific volume was calculated by dividing the volume of the cup by theweight of the powder layer remaining in the cup.

8) Angle of Repose [°]

The water content of powder (measured by means of an infrared moisturemeter (Model FD-220, mfd. by KETT Science Laboratory; 1 g, 105° C.)) wasadjusted to 3.5-4.5%. Thereafter, using a commercial powder physicalproperty measuring machine (Powder Tester Model T-R, mfd. by HosokawaMicron Corporation), the powder fell under the following conditions: ametal funnel (made of a material incapable of generating staticelectricity) with an orifice diameter of 0.8 cm, and vibrationgraduation 1.5. The angles of the ridgelines (the angles of tworidgelines; measurement distance 3°) of a heap formed by the powder weremeasured. The angle of repose [°] was expressed as the average of threemeasurements.

9) Compressibility [%]

Compressibility was calculated by the following equation (3) by usingthe apparent specific volume and apparent tapping specific volumedefined above:Compressibility=100×[(1/apparent tapping specific volume)−(1/apparentspecific volume)]/(1/apparent tapping specific volume)   (3)10) Average Particle Size [μm]

Using a low-tap type sieve shaker (Sieve Shaker Model A, mfd. by TairaKosaku-sho Co., Ltd.) and JIS standard screens (Z8801-1987), 10 g of apowder sample was sieved for 10 minutes to measure the particle sizedistribution. The average particle size was expressed as a particle sizecorresponding to a cumulative weight percentage of 50%.

11) Water Vapor Specific Surface Area [m²/g]

Using a dynamic water vapor adsorption apparatus DVS-1 (mfd. by SurfaceMeasurement Systems Ltd.) and water vapor as an adsorption gas, theamount of water vapor adsorbed by a sample was measured in a range of0-30% RH according to the measuring steps described below, and the watervapor specific surface area was calculated by a BET method. Thecalculation was carried out by taking the molecular occupied area ofwater as 8.1 Å. As the sample, 0.01-0.02 g of a sample obtained byremoving water from about 0.10 g of cellulose powder by vacuum drying in5-cm³ sample tube at 100° C. for 3 hours was placed in the aforesaidapparatus and subjected to the measurement.

(Measuring Steps)

The sample was allowed to stand at each of the following relativehumidities for the following measurement time and the amount of watervapor adsorbed onto the sample was measured.

Relative humidity Measurement time 0% RH 200 min. or less 3% RH 150 min.or less 6, 9, 12, 15, 18, 21, 24, 27 or 30% RH 100 min. or less.12) Nitrogen Adsorption Specific Surface Area [m²/g]

Measured by a BET method using a Flowsorb II2300 manufactured byShimadzu Corp. and nitrogen as an adsorption gas.

13) Average Yield Pressure [MPa]

The water content (measured by means of an infrared moisture meter(Model FD-220, mfd. by KETT Science Laboratory; 1 g, 105° C.)) of powderwas adjusted to 3.5-4.5%. Then, 0.5 g of a sample of the powder wasplaced in a die (manufactured by Kikusui Seisakusho Ltd. from materialSUK 2,3) and compressed with a flat punch having a base area of 1 cm²(manufactured by Kikusui Seisakusho Ltd. from material SUK 2,3) untilthe pressure became 10 MPa (a compressing machine PCM-1A manufactured byAikoh Engineering Co., Ltd. was used and the compression rate wasadjusted to 1 cm/min). A stress P and the height h [cm] of the powderlayer at the stress P were input into a computer at a data input rate of0.02 second and recorded therein.

The relationship between the stress P and In[1/(1−D)] calculated fromthe volume V [cm³] of the powder layer at the stress P was graphicallyillustrated, followed by linear regression in a stress P [MPa] range of2-10 MPa by a method of least squares. The average yield pressure wasdefined as the reciprocal number of the slope k of the regression line.V [cm³] was expressed as the product of the base area (1 cm²) of thepunch with a flat surface and the height h [cm] of the powder layer atthe stress P. The height h of the powder layer should be measuredwithout strain in the system of the compressing machine (the totalstrain in the die, punch, load cell, plunger, etc.). D was calculated bythe following equation (4):D=[(0.5×(1−W/100))/V]/1.59   (4)wherein D is the packing rate of tablets, W is the water content [%]measured by means of an infrared moisture meter (Model FD-220, mfd. byKETT Science Laboratory; 1 g, 105° C.), and the value 1.59 is the truedensity [g/cm³] of the cellulose powder measured with an air comparisontype gravimeter (Pycnometer 930, mfd. by Beckmann AG).14) Water Vapor Adsorption Rate of Tablets Ka [1/min]

A cylindrical molded product with a diameter of 0.8 cm obtained bycompressing 0.05 g of a sample at 90 MPa for 10 seconds (a compressingmachine PCM-1A manufactured by Aikoh Engineering Co., Ltd. was used andthe compression rate was adjusted to 29 cm/min) was immersed inacetonitrile (for liquid chromatography) for 48 hours, placed in adynamic vapor adsorption measurement apparatus (Model DVS-1, mfd. byMicrotec Nichion Co., Ltd.), and then dried at 25° C. and a relativehumidity of 0% RH in a nitrogen stream until the tablet weight reachedsufficient equilibrium (the degree of variability of the weight for 5minutes was 0.0015%/min or less). Then, the relative humidity was set at55% RH, and the tablet weight was recorded every 1 minute until thetablet weight reached equilibrium (the degree of variability of theweight for 5 minutes was 0.0015%/min or less). The relationship betweenthe water vapor adsorption time t and In[θe/(θe−θ)] was graphicallyillustrated, followed by linear regression in a range of 20-100 minutesby a method of least squares. The slope of the regression line was takenas Ka. The saturated water vapor adsorption rate θe[%] of the tablet ata relative humidity of 55% RH and the water vapor adsorption rate θ[%]of the tablet at a relative humidity of 55% RH and a water vaporadsorption time of t were calculated as follows:θe=100×ms/m ₀ [%]  (5)θ=100×mt/m ₀   (6)wherein m₀ is a tablet weight [g] at the time when equilibrium wassufficiently reached at a relative humidity of 0% RH, mt is a tabletweight [g] at a relative humidity of 55% RH and a water vapor adsorptiontime of t, and ms is a tablet weight [g] at the time when equilibriumwas sufficiently reached at a relative humidity of 55% RH.15) Hardness [N]

Using a Schleuniger hardness meter (Model 6D, mfd. by Freund SangyoK.K.), a load was applied to a cylindrical molded product or a tablet inthe direction of diameter, and a load at the time of the destructionthereof was measured. The hardness was expressed as the number averageof load values obtained for five samples. A cylindrical molded productof 100% cellulose powder and a cylindrical molded product of a Mixtureof equal amounts of cellulose powder and lactose were produced asfollows. In a die (manufactured by Kikusui Seisakusho Ltd. from materialSUK 2,3) was placed 0.5 g of a sample, and compressed with a flat punchhaving a diameter of 1.13 cm (base area: 1 cm²) (manufactured by KikusuiSeisakusho Ltd. from material SUK 2,3). The cylindrical molded productof 100% cellulose powder was produced by compression at 20 MPa andmaintenance of the compression stress for 10 seconds (a compressingmachine PCM-1A manufactured by Aikoh Engineering Co., Ltd. was used andthe compression rate was adjusted to about 10 cm/min). The cylindricalmolded product of a mixture of equal amounts of cellulose powder andlactose was produced by compression at 80 MPa and maintenance of thecompression stress for 10 seconds (a compressing machine PCM-1Amanufactured by Aikoh Engineering Co., Ltd. was used and the compressionrate was adjusted to about 25 cm/min).

16) Disintegration Time [Seconds]

A disintegration test was carried out according to the general testmethod and tablet disintegration test method prescribed in the 13threvised Japanese Pharmacopoeia. The disintegration time of cylindricalmolded articles or tablets in pure water at 37° C. was measured by meansof a disintegration tester (Model NT-40HS, mfd. by Toyama Sangyo Co.,Ltd., fitted with a disc). The disintegration time was expressed as thenumber average of values measured for six samples.

17) CV Value of Tablets [%]

Ten tablets were accurately weighed and the CV value was defined as thecoefficient of variation of the tablet weight.

18) Degree of Wear of Tablets [%]

The weight (Wa) of 20 tablets was measured, and the tablets were placedin a tablet degree-of-wear tester (mfd. by PTFR-A, PHARMA TEST),followed by revolution at 25 rpm for 4 minutes. Then, fine powderadhering to the tablets was removed and the weight (Wb) of the tabletswas measured again. The degree of wear was calculated by the equation(7):Degree of wear=100×(Wa−Wb)/Wa   (7)19) Rate of Dissolution of a Drug (%)

The rate of dissolution is measured by a paddle method by using anautomatic dissolution tester DT-610 (mfd. by Nippon Bunko Kogyo Co.,Ltd.). As a test liquid, the first liquid among the test liquids in thegeneral test method and degradation test method prescribed in the 13threvised Japanese Pharmacopoeia. The measurement was carried out threetimes and the average of the measured values was calculated.

COMPARATIVE EXAMPLE 1′

Two kilograms of commercially available SP pulp (polymerization degree:1030, and level-off polymerization degree: 220) was chopped, placed in30 L of a 4N aqueous hydrochloric acid solution, and then hydrolyzed at60° C. for 72 hours with stirring (rate of stirring: 10 rpm) by alow-rate stirrer (30LGL reactor, mfd. by Ikebukuro Hohroh Kogyo Co.,Ltd.; blade diameter: about 30 cm). The resulting acid-insoluble residuewas filtered by the use of a Buchner funnel, and the filtration residuewas washed 4 times with 70 L of pure water, neutralized with aqueousammonia, and then placed in a 90-L polyethylene bucket. Pure water wasadded thereto and the resulting mixture was made into a cellulosedispersion having a concentration of 10% (pH: 6.7, and IC: 45 μS/cm),while being stirred (rate of stirring: 100 rpm) with Three-One Motor(Type 1200G, 8M/M, mfd. by HEIDON; blade diameter: about 5 cm).

The cellulose dispersion was subjected to spray drying (dispersion feedrate 6 L/hr, inlet temperature 180 to 220° C., and outlet temperature 50to 70° C.) to obtain cellulose powder A (loss in weight on drying:3.5%). Table 1 shows physical properties of cellulose powder A andphysical properties of a cylindrical molded product obtained bycompressing 100% cellulose powder A. Table 2 shows physical propertiesof a cylindrical molded product obtained by compressing a mixture ofequal amounts of cellulose powder A and lactose.

EXAMPLE 2

Cellulose powder B (loss in weight on drying: 4.2%) was obtained by thesame procedure as in Comparative Example 1′ except for usingcommercially available SP pulp (polymerization degree: 790, andlevel-off polymerization degree: 220) and changing the hydrolysisconditions to: 4N, 40° C. and 48 hours, the concentration of thecellulose dispersion to 8%, its pH to 6.0, and its IC to 35 μS/cm. Table1 shows physical properties of cellulose powder B obtained and physicalproperties of a cylindrical molded product obtained by compressing 100%cellulose powder B. Table 2 shows physical properties of a cylindricalmolded product obtained by compressing a mixture of equal amounts ofcellulose powder B and lactose.

EXAMPLE 3

Cellulose powder C (loss in weight on drying: 3.8%) was obtained by thesame procedure as in Example 2 except for changing the rate of stirringduring the reaction to 5 rpm, the concentration of the cellulosedispersion to 12% (rate of stirring for preparing the dispersion: 50rpm), its pH to 6.5, and its IC to 40 μS/cm. Table 1 shows physicalproperties of cellulose powder C obtained and physical properties of acylindrical molded product obtained by compressing 100% cellulose powderC. Table 2 shows physical properties of a cylindrical molded productobtained by compressing a mixture of equal amounts of cellulose powder Cand lactose.

EXAMPLE 4

Cellulose powder D (loss in weight on drying: 3.2%) was obtained by thesame procedure as in Example 2 except for changing the concentration ofthe cellulose dispersion to 16%, its pH to 6.9, and its IC to 65 μS/cm.Table 1 shows physical properties of cellulose powder D obtained andphysical properties of a cylindrical molded product obtained bycompressing 100% cellulose powder D. Table 2 shows physical propertiesof a cylindrical molded product obtained by compressing a mixture ofequal amounts of cellulose powder D and lactose.

EXAMPLE 5

Cellulose powder E (loss in weight on drying: 4.0%) was obtained by thesame procedure as in Example 2 except for changing the hydrolysisconditions to a 3N aqueous hydrochloric acid solution, 40° C. and 40hours, the concentration of the cellulose dispersion to 8%, its pH to6.3, and its IC to 38 μS/cm. Table 1 shows physical properties ofcellulose powder E obtained and physical properties of a cylindricalmolded product obtained by compressing 100% cellulose powder E. Table 2shows physical properties of a cylindrical molded product obtained bycompressing a mixture of equal amounts of cellulose powder E andlactose.

EXAMPLE 6

Cellulose powder F was obtained by the same procedure as in ComparativeExample 1′ except for using commercial SP pulp (polymerization degree:870, and level-off polymerization degree: 220), and changing thehydrolysis conditions to a 3N aqueous hydrochloric acid solution, 40° C.and 24 hours, the rate of stirring during the reaction to 15 rpm, theconcentration of the cellulose dispersion to 8%, its pH to 5.7, and itsIC to 30 μS/cm. Table 1 shows physical properties of cellulose powder Fobtained and physical properties of a cylindrical molded productobtained by compressing 100% cellulose powder F. Table 2 shows physicalproperties of a cylindrical molded product obtained by compressing amixture of equal amounts of cellulose powder F and lactose.

EXAMPLE 7

Cellulose powder G was obtained by the same procedure as in ComparativeExample 1′ except for changing the hydrolysis conditions to a 3N aqueoushydrochloric acid solution, 40° C. and 20 hours, the rate of stirringduring the reaction to 20 rpm, the concentration of the cellulosedispersion to 6%, it pH to 7.1, and its IC to 180 μS/cm. Table 1 showsphysical properties of cellulose powder G obtained and physicalproperties of a cylindrical molded product obtained by compressing 100%cellulose powder G. Table 2 shows physical properties of a cylindricalmolded product obtained by compressing a mixture of equal amounts ofcellulose powder G and lactose.

COMPARATIVE EXAMPLE 1

Commercial SP pulp (polymerization degree: 790, and level-offpolymerization degree: 220) was hydrolyzed in 30 L of a 3N aqueoushydrochloric acid solution at 105° C. for 30 minutes with stirring (rateof stirring: 30 rpm) by a low-rate stirrer (30LGL reactor, mfd. byIkebukuro Hohroh Kogyo Co., Ltd.; blade diameter: about 30 cm). Theresulting acid-insoluble residue was filtered by the use of a Buchnerfunnel, and the filtration residue was washed 4 times with 70 L of purewater, neutralized with aqueous ammonia, and then placed in a 90-Lpolyethylene bucket. Pure water was added thereto and the resultingmixture was made into a cellulose dispersion having a concentration of17% (pH: 6.4, and IC: 120 μS/cm), while being stirred (rate of stirring:500 rpm) with a Three-One Motor (Type 1200G, 8M/M, mfd. by HEIDON; bladediameter: about 5 cm).

The cellulose dispersion was dried in a drum dryer (Model KDD-1 ofKusunoki Seisakusho Co., Ltd., steam pressure: 0.35 MPa, drum surfacetemperature: 136° C., number of revolutions of drum: 2 rpm, andtemperature of the dispersion in a reservoir: 100° C.) and then groundwith a hammer mill, and coarse particles were removed by a screen withopening of 425 μm to obtain cellulose powder H (loss in weight ondrying: 3.9%, corresponding to Example 1 described in JP-A-6-316535).Table 1 shows physical properties of cellulose powder H obtained andphysical properties of a cylindrical molded product obtained bycompressing cellulose powder H. Table 2 shows physical properties of acylindrical molded product obtained by compressing a mixture of equalamounts-of cellulose powder H and lactose.

COMPARATIVE EXAMPLE 2

Two kilograms of commercial SP pulp (polymerization degree: 1030, andlevel-off polymerization degree: 220) was chopped and then hydrolyzed in30 L of a 0.14N aqueous hydrochloric acid solution at 121° C. for 1 hourwith stirring (rate of stirring: 30 rpm) by a low-rate stirrer (30LGLreactor, mfd. by Ikebukuro Hohroh Kogyo Co., Ltd.; blade diameter: about30 cm). The resulting acid-insoluble residue was filtered by the use ofa Buchner funnel, and the filtration residue was washed 4 times with 70L of pure water, neutralized with aqueous ammonia, placed in a 90-Lpolyethylene bucket, and then made into a cellulose dispersion having aconcentration of 17% (pH: 6.4, and IC: 64 μS/cm), while being stirred(rate of stirring: 500 rpm) with a Three-One Motor (Type 1200G, 8M/M,mfd. by HEIDON; blade diameter: about 5 cm).

The cellulose dispersion was subjected to spray drying (dispersion feedrate: 6 L/hr, inlet temperature: 180 to 220° C., and outlet temperature:70° C.), after which coarse particles were removed by a 325-mesh screento obtain cellulose powder I (loss in weight on drying: 4.1%,corresponding to Example 1 in JP-B-40-26274). Table 1 shows physicalproperties of cellulose powder I obtained and physical properties of acylindrical molded product obtained by compressing cellulose powder I.Table 2 shows physical properties of a cylindrical molded productobtained by compressing a mixture of equal amounts of cellulose powder Iand lactose.

COMPARATIVE EXAMPLE 3

A pulp sheet of needle leaf tree and broad-leaf tree for dissolution(α-cellulose 90.5%, β-cellulose 4.7%, cuprammonium relative viscosity4.70, and whiteness 93) was disintegrated, immersed in 12 L of a sodiumhypochlorite solution (available chloride: 1.6 g/L) to adjust the pH to10.9, and then treated at 60° C. for 310 minutes. The pulp thus treatedwas thoroughly washed with water, centrifugally dehydrated, and thendried by air blowing at 105° C. The pulp dried was ground with anoscillating ball mill for 30 minutes, after which coarse particles wereremoved with a 100-mesh screen to obtain cellulose powder J (loss inweight on drying: 2.0%, corresponding to Example 2 in JP-A-50-19917).Table 1 shows physical properties of cellulose powder J obtained andphysical properties of a cylindrical molded product obtained bycompressing cellulose powder J. Table 2 shows physical properties of acylindrical molded product obtained by compressing a mixture of equalamounts of cellulose powder J and lactose.

COMPARATIVE EXAMPLE 4

Commercial KP pulp (polymerization degree: 840, and level-offpolymerization degree: 145) was hydrolyzed in a 0.7% aqueoushydrochloric acid solution at 125° C. for 150 minutes, and thehydrolysis residue was neutralized, washed and then filtered to obtain awet cake. The wet cake was thoroughly ground in a kneader, after whichethanol was added thereto so that the volume ratio of ethanol to theground product of the cake becomes 1. The resulting mixture was filteredby expression and then air-dried. The resulting dried powder was groundwith a hammer mill and coarse particles were removed with a 40-meshscreen to obtain cellulose powder K (loss in weight on drying: 3.0%,corresponding to Example 1 in JP-A-56-2047). Table 1 shows physicalproperties of cellulose powder K obtained and physical properties of acylindrical molded product obtained by compressing cellulose powder K.Table 2 shows physical properties of a cylindrical molded productobtained by compressing a mixture of equal amounts of cellulose powder Kand lactose.

COMPARATIVE EXAMPLE 5

Cellulose powder I of Comparative Example 2 was ground with a pneumaticgrinding mill (Single-Track Jet Mill Model STJ-200, mfd, by SeishinEnterprise Co., Ltd.), and coarse particles were removed by a screenwith a opening of 75 μm to obtain cellulose powder L (loss in weight ondrying: 4.1%, corresponding to Example 1 in JP-A-63-267731). Table 1shows physical properties of cellulose powder L obtained and physicalproperties of a cylindrical molded product obtained by compressingcellulose powder L. Table 2 shows physical properties of a cylindricalmolded product obtained by compressing a mixture of equal amounts ofcellulose powder L and lactose.

COMPARATIVE EXAMPLE 6

Cellulose powder E of Example 5 was ground with a magnetic ball mill tor12 hours to obtain cellulose powder M (loss in weight on drying: 5.1%).Table 1 shows physical properties of cellulose powder M obtained andphysical properties of a cylindrical molded product obtained bycompressing cellulose powder M. Table 2 shows physical properties of acylindrical molded product obtained by compressing a mixture of equalamounts of cellulose powder M and lactose.

COMPARATIVE EXAMPLE 7

The same process as in Comparative Example 2 was carried out except forchanging the hydrolysis conditions to a 3% aqueous hydrochloric acidsolution, 105° C. and 20 minutes. After the filtration and washingisopropyl alcohol was added to the filtration residue washed, and theresidue was dispersed with a Gohrin Homogenizer Model 15M manufacturedby Nihon Seiki Seisakusho Ltd. The solid content of the resultingdispersion was adjusted to 10%, followed by spray drying. Coarseparticles were removed by the use of a screen with opening of 250 μm toobtain cellulose powder N (loss in weight on drying: 3.5%, correspondingto Example 2 in JP-A-2-84401). Table 1 shows physical properties ofcellulose powder N obtained and physical properties of a cylindricalmolded product obtained by compressing cellulose powder N.

Table 2 shows physical properties of a cylindrical molded productobtained by compressing a mixture of equal amounts of cellulose powder Nand lactose.

COMPARATIVE EXAMPLE 8

Using Air Jet Sieve, coarse particles were removed from cellulose powderH of Comparative Example 1 with a 75-μm screen and fine particles wereremoved therefrom with a 38-μm screen to obtain cellulose powder O (lossin weight on drying: 4.0%, corresponding to Example in JP-A-11-152233).Table 1 shows physical properties of cellulose powder O obtained andphysical properties of a cylindrical molded product obtained bycompressing cellulose powder O.

Table 2 shows physical properties of a cylindrical molded productobtained by compressing a mixture of equal amounts of cellulose powder Oand lactose.

COMPARATIVE EXAMPLE 9

The same cellulose dispersion as obtained in Example 5 was stirred (rateof stirring: 4,000 rpm) with a TK homomixer and then subjected to spraydrying (dispersion feed rate: 6 L/hr, inlet temperature: 180 to 220° C.,and outlet temperature: 50 to 70° C.) to obtain cellulose powder P (lossin weight on drying: 3.8%). Table 1 shows physical properties ofcellulose powder P obtained and physical properties of a cylindricalmolded product obtained by compressing cellulose powder P. Table 2 showsphysical properties of a cylindrical molded product obtained bycompressing a mixture of equal amounts of cellulose powder P andlactose.

COMPARATIVE EXAMPLE 10

Commercially available SP pulp (polymerization degree: 790, andlevel-off polymerization degree: 220) was chopped and then hydrolyzed ina 10% aqueous hydrochloric acid solution at 105° C. for 5 minutes, andthe resulting acid-insoluble residue was filtered, washed and thensubjected to pH adjustment and concentration adjustment to obtain acellulose particle dispersion having a solid content of 17%, a pH of 6.4and an electric conductivity of 120 μS/cm. The dispersion was dried in adrum dryer (Model KDD-1, mid. by Kusunoki Kikai Seisakusho Co., Ltd.:steam pressure: 0.35 MPa, drum surface temperature: 136° C., number ofrevolutions of drum: 2 rpm, and temperature of the. dispersion in areservoir: 100° C.) and then ground with a hammer mill, and coarseparticles were removed by the use of a screen with opening of 425 μm toobtain cellulose powder Q (loss in weight on drying: 4.5%, correspondingto Comparative Example 8 in JP-A-6-316535). Table 1 shows physicalproperties of cellulose powder Q obtained and physical properties of acylindrical molded product obtained by compressing cellulose powder Q.Table 2 shows physical properties of a cylindrical molded productobtained by compressing a mixture of equal amounts of cellulose powder Qand lactose.

COMPARATIVE EXAMPLE 11

Ten grams of chopped commercially available SP pulp (polymerizationdegree: 1030, and level-off polymerization degree: 220) was impregnatedwith a 0.25N solution of hydrochloric acid in isopropyl alcohol and thenhydrolyzed at 90° C. for minutes while being stirred so that the shearrate of the starting-material layer became 10 s⁻¹. Then, the hydrolysisresidue was dried on trays at 40° C. for 24 hours to obtain cellulosepowder R (loss in weight on drying: 2.5%, corresponding to Example 8 inRU2050362). Table 1 shows physical properties of cellulose powder Robtained and physical properties of a cylindrical molded productobtained by compressing cellulose powder R. Table 2 shows physicalproperties of a cylindrical molded product obtained by compressing amixture of equal amounts of cellulose powder R and lactose.

EXAMPLE 8

In a polyethylene bag, 20 wt % of cellulose powder C of Example 3, 19.5wt % of lactose (Pharmatose 100M, available from DMV Corp.), 60 wt % ofethenzamide (mfd. by Iwaki Seiyaku Co., Ltd.) and 0.5 wt % of lightsilicic anhydride (Aerosil 200, mfd. by Nippon Aerosil Co., Ltd.) werethoroughly mixed for 3 minutes, and magnesium stearate (mfd. by TaiheiKagaku Sangyo Co., Ltd.) was added thereto in an amount of 0.5 wt %based on the total weight of the mixed powder, followed by slow mixingfor another 30 seconds. Table 3 shows the angle of repose of theresulting mixed powder.

This mixed powder was compressed into tablets each weighing 100 mg witha rotary tabletting machine (CLEANPRESS CORRECT 12HUK, mfd. by KikusuiSeisakusho Ltd.) at a turntable rotational speed of 24 rpm and acompressive force of 3,000 N by the use of a 11R punch with a diameterof 0.6 cm. Table 3 shows physical properties of the tablets.

EXAMPLE 9

Mixed powder and tablets were prepared by the same procedure as inExample 8 except for using cellulose powder E of Example 5. Table 3shows the angle of repose of the mixed powder and physical properties ofthe tablets.

COMPARATIVE EXAMPLE 12

Mixed powder and tablets were prepared by the same procedure as inExample 8 except for using cellulose powder H of Comparative Example 1.Table 3 shows the angle of repose of the mixed powder and physicalproperties of the tablets.

COMPARATIVE EXAMPLE 13

Mixed powder and tablets were prepared by the same procedure as inExample 8 except for using cellulose powder I of Comparative Example 2in Example 8. Table 3 shows the angle of repose of the mixed powder andphysical properties of the tablets.

EXAMPLE 10

In a polyethylene bag, 60 wt % of acetaminophen (fine powder type, mfd.by Yoshitomi Fine Chemical Co., Ltd.) and 0.5 wt % of light silicicanhydride (Aerosil 200, mfd. by Nippon Aerosil Co., Ltd.) were mixed for3 minutes to previously improve the fluidity of the drug. Then, 30 wt %of cellulose powder C of Example 3 and 9.5 wt % of corn starch(available from Nippon Starch Chemical Co., Ltd.) were added thereto,followed by thorough mixing for 3 minutes in the polyethylene bag.Magnesium stearate (mfd. by Taihei Kagaku Sangyo Co., Ltd.) was addedthereto in an amount of 0.5 wt % based on the total weight of the mixedpowder, followed by slow mixing for further 30 seconds. Table 4 showsthe angle of repose of the resulting mixed powder.

This mixed powder was compressed into tablets each weighing 100 mg witha rotary tabletting machine

(CLEANPRESS CORRECT 12HUK, mfd. by Kikusui Seisakusho Ltd.) at aturntable rotational speed of 53 rpm and a compressive force of 5,000 Nby the use of a 11R punch with a diameter of 0.6 cm. Table 4 showsphysical properties of the tablets. As the disintegration time of thetablets, a value obtained without a disc is shown. As the rate ofdissolution of the drug contained in the tablets, a value obtained at anumber of revolutions of a paddle of 100 rpm is shown.

EXAMPLE 11

In a polyethylene bag, 30 wt % of cellulose powder C of Example 3, 9.5wt % of crospovidone (Colidon CL, mfd. by BASF), 60 wt % ofacetaminophen (fine powder type, mfd. by Yoshitomi Fine Chemical Co,Ltd.) and 0.5 wt % of light silicic anhydride (Aerosil 200, mfd. byNippon Aerosil Co., Ltd.) were mixed all at once for 3 minutes.Magnesium stearate (mfd. by Taihei Kagaku Sangyo Co, Ltd.) was addedthereto in an amount of 0.5 wt % based on the total weight of the mixedpowder, followed by slow mixing for further 30 seconds. Table 5 showsthe angle of repose of the resulting mixed powder.

This mixed powder was compressed into tablets each weighing 100 mg witha rotary tabletting machine (CLEANPRESS CORRECT 12HUK, mfd. by KikusuiSeisakusho Ltd.) at a turntable rotational speed of 53 rpm and acompressive force of 5,000 N by the use of a 11R punch with a diameterof 0.6 cm. Table 5 shows physical properties of the tablets. As thedisintegration time of the tablets, a value obtained without a disc isshown.

EXAMPLE 12

In a polyethylene bag, 60 wt % of acetaminophen (fine powder type, mfd.by Yoshitomi Fine Chemical Co., Ltd.) and 0.5 wt % of light silicicanhydride (Aerosil 200, mfd. by Nippon Aerosil Co., Ltd.) were mixed for3 minutes to previously improve the fluidity of the drug. Then, 30 wt %of cellulose powder C of Example 3 and 9.5 wt % of crospovidone (ColidonCL, mfd. by BASF) were added thereto, followed by thorough mixing for 3minutes in the polyethylene bag. Magnesium stearate (mfd. by TaiheiKagaku Sangyo Co., Ltd.) was added thereto in an amount of 0.5 wt %based on the total weight of the mixed powder, followed by slow mixingfor further 30 seconds. Table 5 shows the angle of repose of theresulting mixed powder.

This mixed powder was compressed into tablets each weighing 100 mg witha rotary tabletting machine (CLEANPRESS CORRECT 12HUK, mfd. by KikusuiSeisakusho Ltd.) at a turntable rotational speed of 53 rpm and acompressive force of 5,000 N by the use of a 11R punch with a diameterof 0.6 cm. Table 5 shows physical properties of the tablets. As thedisintegration time of the tablets, a value obtained without a disc isshown.

EXAMPLE 13

The process of Example 12 was repeated except for using cellulose powderE of Example 5. Table 5 shows the angle of repose of the resulting mixedpowder and physical properties of tablets made of the mixed powder.

EXAMPLE14

In a polyethylene bag, 70 wt % of acetaminophen (fine powder type, mfd.by Yoshitomi Fine Chemical Co., Ltd.) and 0.5 wt % of light silicicanhydride (Aerosil 200, mfd. by Nippon Aerosil Co., Ltd.) were mixed for3 minutes to previously improve the fluidity of the drug. Then, 25 wt %of cellulose powder C of Example 3 and 4.5 wt % of sodium croscarmellose(Ac-Di-Sol, mfd. by FMC Corp., sold by Asahi Kasei Co.) were addedthereto, followed by thorough mixing for 3 minutes in the polyethylenebag. Magnesium stearate (mfd. by Taihei Kagaku Sangyo Co., Ltd.) wasadded thereto in an amount of 0.5 wt % based on the total weight of themixed powder, followed by slow mixing for further 30 seconds. Table 6shows the angle of repose of the resulting mixed powder.

This mixed powder was compressed into tablets each weighing 180 mg witha rotary tabletting machine (CLEANPRESS CORRECT 12HUK, mfd. by KikusuiSeisakusho Ltd.) at a turntable rotational speed of 53 rpm and acompressive force of 10,000 N by the use of a 12R punch with a diameterof 0.8 cm. Table 6 shows physical properties of the tablets. As thedisintegration time of the tablets, a value obtained without a disc isshown.

EXAMPLE 15

The process of Example 14 was repeated except for using cellulose powderE of Example 5. Table 6 shows the angle of repose of the resulting mixedpowder and physical properties of tablets made of the mixed powder. Asthe disintegration time of the tablets, a value obtained without a discis shown.

COMPARATIVE EXAMPLE 14

The process of Example 10 was repeated except for using cellulose powderH of Comparative Example 1. Table 4 shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown. As the rate of dissolution of the drugcontained in the tablets, a value obtained at a number of revolutions ofa paddle of 100 rpm is shown.

COMPARATIVE EXAMPLE 15

The process of Example 10 was repeated except for using cellulose powder1 of Comparative Example 2.

Table 4 shows the angle of repose of the resulting mixed powder andphysical properties of tablets made of the mixed powder. As thedisintegration time of the tablets, a value obtained without a disc isshown. As the rate of dissolution of the drug contained in the tablets,a value obtained at a number of revolutions of a paddle of 100 rpm isshown.

COMPARATIVE EXAMPLE 16

The process of Example 11 was repeated except for using cellulose powderH of Comparative Example 1. Table 5 shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown.

COMPARATIVE EXAMPLE 17

The process of Example 11 was repeated except for using cellulose powderI of Comparative Example 2. Table S shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown.

COMPARATIVE EXAMPLE 18

The process of Example 12 was repeated except for using cellulose powderH of Comparative Example 1. Table 5 shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown.

COMPARATIVE EXAMPLE 19

The process of Example 12 was repeated except for using cellulose powderI of Comparative Example 2. Table 5 shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown.

COMPARATIVE EXAMPLE 20

The process of Example 14 was repeated except for using cellulose powderH of Comparative Example 1. Table 6 shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown.

COMPARATIVE EXAMPLE 21

The process of Example 14 was repeated except for using cellulose powderI of Comparative Example 2. Table 6 shows the angle of repose of theresulting mixed powder and physical properties of tablets made of themixed powder. As the disintegration time of the tablets, a valueobtained without a disc is shown.

EXAMPLE 16

(Preparation of Nucleus Particles)

Into a rolling fluidized-bed coating apparatus (“Multiplex” Model MP-01,mfd. by Powrex; using a Wurster column with side air) was charged 0.7 kgof trimebutin maleate (available from Sumitomo Eine Chem. Co., Ltd.),and sprayed with a 5 wt % hydroxypropylmethyl cellulose (TC-5E,available from Shin-etsu Chemical Co., Ltd.) binder solution (spray airpressure: 0.13 MPa, spray air flow rate: 35 L/min, side air pressure:0.10 MPa, charged air temperature: 75° C., exhaust temperature: 37° C.,air flow rate: 40 m³/hr, and binder solution feed rate: 7 g/min) untilits proportion becomes 3 wt % (in terms of solids) based on the weightof trimebutin maleate, followed by pre-granulation. Coarse particleswere removed from the pre-granulation product by the use of a screenhaving opening of 250 μm, and 0.7 kg of the residue was charged into theaforesaid coating apparatus and sprayed with a film coating liquidconsisting of 38.1 wt % of an aqueous ethyl cellulose dispersion(“Aquacoat” ECD-30, mfd. by FMC Corp., sold by Asahi Chemical IndustryCo.; solid content 30 wt %), 2.9 wt % of triacetin, 38.1 wt % of a 15 wt% aqueous mannitol solution and 20.9 wt % of water (spray air pressure:0.10 MPa, spray air flow rate: 30 L/min, side air pressure: 0.02 MPa,charged air temperature: 70° C., exhaust temperature: 36° C., air flowrate: 40 m³/hr, and film-coating liquid feed rate: 8 g/min) until itsproportion becomes 30 wt % (in terms of solids) based on the weight ofthe trimebutin maleate pre-granulation product to obtain coatedgranules. The coated granules were dried on trays at 40° C. for 30minutes and then subjected to curing (film formation by heating)treatment by drying on trays at 80° C. for 60 minutes to obtain nucleusparticles A. Table 7 shows the rate of dissolution of trimebutin maleatein nucleus particles A after 1 minute.

(Preparation of Nucleus Particle-Containing Tablets)

In a the (manufactured by Kikusui Seisakusho Ltd. from material SUK 2,3)was placed 0.2 g of a sample consisting of 59 wt % of cellulose powder Bof Example 2, 26 wt % of nucleus particles A and 15 wt % of sodiumcroscarmellose (Ac-Di-Sol, mfd. by FMC Corp., sold by Asahi Kasei Co.),and compressed with a flat punch having a diameter of 0.8 cm(manufactured by Kikusui Seisakusho Ltd. from material SUK 2,3). Thecompression stress was maintained at 1,400 N for 10 seconds to obtainnucleus particle-containing tablets A. As a compressing machine, PCM-1Amanufactured by Aikoh Engineering Co., Ltd. was used. Table 7 shows thetablet hardness of nucleus particle-containing tablets A and the rate ofdissolution of trimebutin maleate in nucleus particle-containing tabletsA after 1 minute.

EXAMPLE 17

Nucleus particle-containing tablets B were obtained by the sameprocedure as in Example 16 except for changing their composition and thecompression stress as follows; cellulose powder B of Example 2: 59 wt %,nucleus particles A: 26 wt %, corn starch: 10 wt %, sodiumcroscarmellose: 5 wt %, and compression stress: 1,500 N. Table 7 showsthe tablet hardness of nucleus particle-containing tablets B and therate of dissolution of trimebutin maleate in nucleus particle-containingtablets B after 1 minute.

EXAMPLE 18

Nucleus particle-containing tablets C were obtained by the sameprocedure as in Example 16 except for changing their composition asfollows; cellulose powder B of Example 2: 59 wt %, nucleus particles A:26 wt %, partly pregelatinized starch (“PCS” PC-10, available from AsahiKasei Co.): 10 wt %, and sodium croscarmellose: 5 wt %. Table 7 showsthe tablet hardness of nucleus particle-containing tablets C and therate of dissolution of trimebutin maleate in nucleus particle-containingtablets C after 1 minute.

EXAMPLE 19

(Preparation of Nucleus Particles)

A spherical nucleus (“Celfia” CP-305, available from Asahi Kasei Co.)was charged into a rolling fluidized-bed coating apparatus (“Multiplex”Model MP-25, mfd. by Powrex) and sprayed with a drug-coating solutionconsisting of 10 parts of riboflavin, 2 wt % of hydroxypropyl cellulose(L type, available from Nippon Soda Co., Ltd.) and 88 wt % of water, toobtain layering granules containing 2 wt % of riboflavin. Into a rollingfluidized-bed coating apparatus (“Multiplex” Model MP-01, mfd. byPowrex) was charged 1.5 kg of the layering granules, and sprayed with afilm coating liquid consisting of 32.0 wt % of an aqueous ethylcellulose dispersion (“Aquacoat” ECD-30, mfd. by FMC Corp., sold byAsahi Kasei Co.; solid content 30 wt %), 2.4 wt % of triethyl citrate,30 wt % of a 10 wt % aqueous hydroxypropylmethyl cellulose solution and35.6 wt % of water (spray air pressure: 0.16 MPa, spray air flow rate:40 L/min, charged air temperature: 75° C., exhaust temperature: 36° C.,air flow rate: 75 m³/hr, and film-coating liquid feed rate: 21 g/min)until its proportion becomes 50 wt % (in terms of solids) based on theweight of the layering granules to obtain coated granules. The coatedgranules were dried on trays at 50° C. for 30 minutes and then subjectedto curing (film formation by heating) at 80° C. for 60 minutes to obtainnucleus particles B. Table 8 shows the rate of dissolution of riboflavinin nucleus particles B after 30 minutes.

(Preparation of Nucleus Particle-Containing Tablets)

Nucleus particle-containing tablets D were obtained by the sameprocedure as in Example 16 except for changing their composition and thecompression stress as follows; cellulose powder B of Example 2: 50parts, nucleus particles B: 45 parts, sodium croscarmellose: 5 parts,and compression stress: 2,200 N. Table 8 shows the tablet hardness ofnucleus particle-containing tablets D and the rate of dissolution ofriboflavin in nucleus particle-containing tablets D after 30 minutes.

COMPARATIVE EXAMPLE 22

Nucleus particle-containing tablets E were obtained by the sameprocedure as in Example 16 except for using cellulose powder H ofComparative Example 1. Table 7 shows the tablet hardness of nucleusparticle-containing tablets E. Nucleus particle-containing tablets Ewere hardly disintegrated in a dissolution test, so that the rate ofdissolution of trimebutin maleate in nucleus particle-containing tabletsE could not be measured.

COMPARATIVE EXAMPLE 23

Nucleus particle-containing tablets F were obtained by the sameprocedure as in Example 16 except for using cellulose powder I ofComparative Example 2 and changing the compression stress to 1,700 N.Table 7 shows the tablet hardness of nucleus particle-containing tabletsF and the rate of dissolution of trimebutin maleate in nucleusparticle-containing tablets F after 1 minute.

COMPARATIVE EXAMPLE 24

Nucleus particle-containing tablets G were obtained by the sameprocedure as in Example 17 except for using cellulose powder I ofComparative Example 2 and changing the compression stress to 2,000 N.Table 7 shows the tablet hardness of nucleus particle-containing tabletsG and the rate of dissolution of trimebutin maleate in nucleusparticle-containing tablets G after 1 minute.

COMPARATIVE EXAMPLE 25

Nucleus particle-containing tablets H were obtained by the sameprocedure as in Example 18 except for using cellulose powder I ofComparative Example 2 and changing the compression stress to 1,800 N.Table 7 shows the tablet hardness of nucleus particle-containing tabletsH and the rate of dissolution of trimebutin maleate in nucleusparticle-containing tablets H after 1 minute.

COMPARATIVE EXAMPLE 26

Nucleus particle-containing tablets I were obtained by the sameprocedure as in Example 19 except for using cellulose powder I ofComparative Example 2 and changing the compression stress to 3,300 N.Table 8 shows the tablet hardness of nucleus particle-containing tabletsI and the rate of dissolution of riboflavin in nucleusparticle-containing tablets I after 30 minutes.

TABLE 1 Powder physical properties Particles Apparent LD of capable ofLD of Apparent tapping particles remaining particles specific specificCelulose Polymerization before on a 250-μm of 75 μm volume volume powderdegree drying screen [%] or less [cm³/g] [cm³/g] Example 2 B 270 3.4 02.5 4.7 2.7 3 C 270 4.0 1 3.0 5.1 2.8 4 D 270 3.4 4 2.5 4.4 2.6 5 E 3304.6 3 3.5 5.3 2.9 6 F 375 5.0 2 4.0 5.8 3.2 7 G 440 5.3 3 4.3 6.3 3.3Comparative 1′ A 220 3.1 0 2.1 4.1 2.6 Example 1 H 220 2.9 6 2.3 5.4 2.72 I 220 2.9 0 1.8 3.1 2.3 3 J 488 5.8 3 4.7 7.1 2.5 4 K 145 2.5 0 1.62.0 1.6 5 L 220 2.9 0 1.6 5.0 2.3 6 M 330 5.0 0 1.7 2.0 1.5 7 N 220 2.40 1.5 5.7 2.8 8 O 220 2.9 0 2.5 6.3 2.8 9 P 330 2.7 0 1.6 2.9 2.2 10 Q380 5.6 15 4.6 5.5 3.2 11 R 356 2.0 8 1.9 3.6 2.3 Powder physicalporperties Physical properties of a Specific cylindrical molded productof Average Angle surface area 100% cellulose powder particle of [m²/g]Yield Disintegration size repose Water pressure Ka Hardness time [μm][°] vapor Nitrogen [MPa] [1/min] [N] [sec] Example 2 45 48 91 1.2 270.0240 201 55 3 50 50 90 1.4 23 0.0230 252 70 4 105 44 92 1.0 29 0.0250190 35 5 45 51 90 1.5 21 0.0226 310 75 6 49 51 89 1.6 24 0.0222 248 85 738 54 88 1.7 27 0.0215 203 108 Comparative 1′ 48 46 93 1.1 29 0.0270 18515 Example 1 47 56 84 1.9 26 0.0195 191 150 2 49 44 93 1.0 40 0.0306 16112 3 50 65 84 0.9 32 0.0170 188 290 4 40 35 86 0.6 45 0.0350 130 7 5 1257 83 2.3 33 0.0175 177 214 6 19 63 94 0.6 43 0.0405 100 5 7 48 55 8224.1 36 0.0185 190 250 8 50 59 84 2.4 24 0.0188 210 220 9 30 43 92 1.244 0.0266 150 19 10 82 55 84 0.8 35 0.0177 174 218 11 75 46 91 1.5 390.0273 166 15

TABLE 2 Physical properties of a molded product of a mixture of equalamounts of cellulose powder and lactose Disintegration CelluloseHardness time powder [N] [sec] Example 2 B 171 35 3 C 220 52 4 D 161 155 E 281 54 6 F 217 65 7 G 172 72 Comparative 1′ A 154 12 Example 1 H 164130 2 I 131 9 3 J 158 250 4 K 100 6 5 L 144 195 6 M 70 4 7 N 162 215 8 O179 190 9 P 118 15 10 Q 143 202 11 R 132 12

TABLE 3 Powder physical property Tablet properties Angle of Hardness CVvalue Disintegration repose [°] [N] [%] time [sec] Example 8 49 48 0.610 9 45 59 0.7 15 Comparative 12 52 42 1.9 25 Example 13 42 32 0.5 9

TABLE 4 Powder physical Tablet physical properties property Rate ofAngle of Hardness CV value Disintegration dissolution after repose [°][N] [%] time [sec] 5 minutes [%] Example 10 51 62 0.8 15 86.7Comparative 14 58 51 1.2 30 77.4 Example 15 46 34 0.9 10 99.7

TABLE 5 Powder physical property Tablet properties Angle of Hardness CVvalue Disintegration repose [°] [N] [%] time [sec] Example 11 50 66 0.910 12 49 74 0.6 11 13 50 81 0.8 11 Comparative 16 57 55 1.5 12 Example17 46 39 0.9 10 18 56 61 1.1 11 19 45 40 0.8 11

TABLE 6 Powder physical property Tablet physical properties Angle ofHardness CV value Disintegration Degree of repose [°] [N] [%] time [sec]wear [%] Example 14 52 79 0.5 15 0.07 15 53 91 0.7 18 0.02 Comparative20 59 68 1.1 31 0.10 Example 21 48 59 0.5 15 0.70

TABLE 7 Nucleus Rate of particle- dissolution containing Hardness after1 minute tablet [N] [%] Nucleus — — 12.0 particle A Example 16 A 44 19.817 B 41 19.0 18 C 40 21.0 Comparative 22 E 44 — Example 23 F 43 27.2 24G 46 25.5 25 H 45 33.9

TABLE 8 Nucleus Rate of particle- dissolution containing Hardness after1 minute tablet [N] [%] Nucleus — — 7.5 particle B Example 19 D 44 9.8Comparative 26 I 44 17.0 Example

INDUSTRIAL APPLICABILITY

Since the cellulose powder of the present invention is excellent influidity and disintegrating property while retaining a good compressionmoldability, the cellulose powder makes it possible to provide tabletshaving high hardness without retardation of their disintegration,especially, even when the tablets are molded under a high strikingpressure. Furthermore, the cellulose powder makes it possible to providetablets which maintain their uniformity in weight even when their drugcontent is high and have a good balance between hardness anddisintegrating property. Therefore, the cellulose powder of the presentinvention is very useful for miniaturizing, for example, tabletscontaining an active ingredient having a large specific volume, ortablets having a high content of an active ingredient. Moreover, ingranule-containing tablets containing a coated active ingredient, thecellulose powder of the present invention exhibits such an advantagethat the compression molding of the tablets hardly destroys thegranules, hardly damages the coating films of the granules and hardlycause a change in drug-releasing properties.

1. A process for producing cellulose powder, comprising: i) hydrolyzinga cellulosic material in aqueous medium with a solution-stirring forceof 0.01 to 10,000 P/V; to obtain a cellulose dispersion; ii)spray-drying the cellulose dispersion at an exhaust temperature of lessthan 100° C., to produce a cellulose powder having the followingcharacteristics: a) an average polymerization degree of 150-450, whichis 5 to 300 higher than the level-off polymerization degree for thecellulose powder, said level-off polymerization degree being measured bya viscosity method after hydrolysis of the cellulose powder in boiling2.5N hydrochloric acid for 15 minutes; b) an average L/D value forparticles that pass through a 75 μm screen and remain on a 38 μm screenbefore spray drying is 3.0-5.5, and c) an angle of repose that is 55° orless.
 2. The process according to claim 1, wherein the averagepolymerization degree is 230-450.
 3. A cellulose powder obtained by theprocess according to claim
 1. 4. An excipient comprising the cellulosepowder according to claim
 3. 5. A molded product comprising thecellulose powder according to claim
 3. 6. The molded product accordingto claim 5, wherein the molded product is tablets containing one or moreactive ingredients.
 7. The molded product according to claim 6, whereinthe molded product contains the active ingredient(s) in a proportion of30 wt % or more.
 8. The molded product according to claim 5, wherein themolded product is coated.
 9. The molded product according to claim 5,wherein the molded product is rapidly disintegrable.
 10. The moldedproduct according to claim 5, wherein the molded product contains afluidizing agent.
 11. A cellulose powder obtained by the processaccording to claim
 2. 12. A process for producing cellulose powder,comprising: spray-drying a cellulose dispersion, which has been exposedto hydrolysis in an aqueous medium with a solution-stirring force of0.01 to 10,000 P/V, at an exhaust temperature of less than 100° C., toproduce a cellulose powder having the following characteristics: a) anaverage polymerization degree of 150-450, which is 5 to 300 higher thanthe level-off polymerization degree for the cellulose powder, saidlevel-off polymerization degree being measured by a viscosity methodafter hydrolysis of the cellulose powder in boiling 2.5N hydrochloricacid for 15 minutes; b) an average L/D value for particles that passthrough a 75 μm screen and remain on a 38 μm screen before spray dryingis 3.0-5.5, and c) an angle of repose that is 55° or less.